6-cycloalkyl-pyrazolopyrimidinones for the treatment of CNS disorders

ABSTRACT

The invention relates to novel 6-Cycloalkyl-pyrazolopyrimidinones according to formula (I). 
                         
wherein R 1  is a 5 or 6 membered aromatic heteroaryl-group, R 2  is an optional substituent, D is optionally substituted cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl or 2-, 3- or 4-pyridyl, m=1 or 2 and n is 0, 1 or 2.
 
     The new compounds are for use as the active entity of medicaments or for the manufacture of medicaments respectively, in particular medicaments for the treatment of conditions concerning deficits in perception, concentration, learning or memory. Such conditions may for example be associated with Alzheimer&#39;s disease, schizophrenia and other diseases. The new compounds are also for example for the manufacture of medicaments and/or for use in the treatment of these diseases, in particular for cognitive impairment associated with such disease. The compounds of the invention show PDE9 inhibiting properties.

The invention relates to novel pyrazolopyrimidinones according toformula (I)

wherein R¹ is a 5 or 6 membered aromatic heteroaryl-group, R² is anoptional substituent, D is optionally substituted cyclopentyl,cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl or 2-, 3- or 4-pyridyl,m=1 or 2 and n is 0, 1 or 2.

The new compounds are for use as the active entity of medicaments or forthe manufacture of medicaments respectively, in particular medicamentsfor the treatment of conditions concerning deficits in perception,concentration, learning or memory. Such conditions may for example beassociated with Alzheimer's disease, schizophrenia and other diseases.The new compounds are also for example for the manufacture ofmedicaments and/or for use in the treatment of these diseases, inparticular for cognitive impairment associated with such disease. Thecompounds of the invention show PDE9 inhibiting properties.

BACKGROUND OF THE INVENTION

The inhibition of phosphodiesterase 9A (PDE9A) is one of the currentconcepts to find new access paths to the treatment of cognitiveimpairments due to CNS disorders like Alzheimer's disease, schizophreniaand other diseases or due to any other neurodegenerative process of thebrain. With the present invention, new compounds that follow thisconcept are presented.

Phosphodiesterase 9A is one member of the wide family ofphosphodiesterases. These enzymes modulate the levels of the cyclicnucleotides 5′-3′ cyclic adenosine monophosphate (cAMP) and 5′-3′ cyclicguanosine monophosphate (cGMP). These cyclic nucleotides (cAMP and cGMP)are important second messengers and therefore play a central role incellular signal transduction cascades. Each of them reactivates interalia, but not exclusively, protein kinases. The protein kinase activatedby cAMP is called protein kinase A (PKA) and the protein kinaseactivated by cGMP is called protein kinase G (PKG). Activated PKA andPKG are able in turn to phosphorylate a number of cellular effectorproteins (e.g. ion channels, G-protein-coupled receptors, structuralproteins, transcription factors). It is possible in this way for thesecond messengers cAMP and cGMP to control a wide variety ofphysiological processes in a wide variety of organs. However, the cyclicnucleotides are also able to act directly on effector molecules. Thus,it is known, for example, that cGMP is able to act directly on ionchannels and thus is able to influence the cellular ion concentration(review in: Wei et al., Prog. Neurobiol., 1998, 56, 37-64). Thephosphodiesterases (PDE) are a control mechanism for the activity ofcAMP and cGMP and thus in turn for the corresponding physiologicalprocesses. PDEs hydrolyse the cyclic monophosphates to the inactivemonophosphates AMP and GMP. Currently, 11 PDE families have been definedon the basis of the sequence homology of the corresponding genes.Individual PDE genes within a family are differentiated by letters (e.g.PDE1A and PDE1B). If different splice variants within a gene also occur,then this is indicated by an additional numbering after the letters(e.g. PDE1A1).

Human PDE9A was cloned and sequenced in 1998. The amino acid identitywith other PDEs does not exceed 34% (PDE8A) and is never less than 28%(PDE5A). With a Michaelis-Menten constant (Km) of 170 nanomolar (nM),PDE9A has high affinity for cGMP. In addition, PDE9A is selective forcGMP (Km for cAMP=230 micromolar (μM)). PDE9A has no cGMP bindingdomain, suggesting that the enzyme activity is not regulated by cGMP. Itwas shown in a Western blot analysis that PDE9A is expressed in humansinter alia in testes, brain, small intestine, skeletal muscle, heart,lung, thymus and spleen. The highest expression was found in the brain,small intestine, kidney, prostate, colon and spleen (Fisher et al., J.Biol. Chem., 1998, 273 (25), 15559-15564; Wang et al., Gene, 2003, 314,15-27). The gene for human PDE9A is located on chromosome 21q22.3 andcomprises 21 exons. 4 alternative splice variants of PDE9A have beenidentified (Guipponi et al., Hum. Genet., 1998, 103, 386-392). ClassicalPDE inhibitors do not inhibit human PDE9A. Thus, IBMX, dipyridamole,SKF94120, rolipram and vinpocetine show no inhibition on the isolatedenzyme in concentrations of up to 100 micromolar (μM). An IC50 of 35micromolar (μM) has been demonstrated for zaprinast (Fisher et al., J.Biol. Chem., 1998, 273 (25), 15559-15564).

Murine PDE9A was cloned and sequenced in 1998 by Soderling et al. (J.Biol. Chem., 1998, 273 (19), 15553-15558). This has, like the humanform, high affinity for cGMP with a Km of 70 nanomolar (nM).Particularly high expression was found in the mouse kidney, brain, lungand liver. Murine PDE9A is not inhibited by IBMX in concentrations below200 micromolar either; the IC50 for zaprinast is 29 micromolar(Soderling et al., J. Biol. Chem., 1998, 273 (19), 15553-15558). It hasbeen found that PDE9A is strongly expressed in some regions of the ratbrain. These include olfactory bulb, hippocampus, cortex, basal gangliaand basal forebrain (Andreeva et al., J. Neurosci., 2001, 21 (22),9068-9076). The hippocampus, cortex and basal forebrain in particularplay an important role in learning and memory processes. As alreadymentioned above, PDE9A is distinguished by having particularly highaffinity for cGMP. PDE9A is therefore active even at low physiologicalconcentrations, in contrast to PDE2A (Km=10 micromolar (μM); Martins etal., J. Biol. Chem., 1982, 257, 1973-1979), PDE5A (Km=4 micromolar (μM);Francis et al., J. Biol. Chem., 1980, 255, 620-626), PDE6A (Km=17micromolar (μM); Gillespie and Beavo, J. Biol. Chem., 1988, 263 (17),8133-8141) and PDE11A (Km=0.52 micromolar (μM); Fawcett et al., Proc.Nat. Acad. Sci., 2000, 97 (7), 3702-3707). In contrast to PDE2A(Murashima et al., Biochemistry, 1990, 29, 5285-5292), the catalyticactivity of PDE9A is not increased by cGMP because it has no GAF domain(cGMP-binding domain via which the PDE activity is allostericallyincreased) (Beavo et al., Current Opinion in Cell Biology, 2000, 12,174-179). PDE9A inhibitors may therefore lead to an increase in thebaseline cGMP concentration.

This outline will make it evident that PDE9A engages into specificphysiological processes in a characteristic and unique manner, whichdistinguishes the role of PDE9A characteristically from any of the otherPDE family members.

WO 2004/099210 discloses 6-arylmethyl-substituted pyrazolopyrimidinoneswhich are PDE9 inhibitors.

WO 2004/099211 discloses 6-cyclylmethyl- and 6-alkylmethyl-substitutedpyrazolopyrimidines and their use for the improvement of cognition,concentration etc.

DE 102 38 722 discloses the use of PDE9A-inhibitors for the improvementof cognition, concentration.

WO 2004/018474 discloses phenyl-substituted pyrazolopyrimidines andtheir use for the improvement of perception, concentration learningand/or memory.

WO 2004/026876 discloses alkyl-substituted pyrazolopyrimidines which andtheir use for the improvement of awareness, concentration learningcapacity and/or memory performance.

WO 2004/096811 discloses heterocyclic bicycles as PDE9 inhibitors forthe treatment of diabetes, including type 1 and type 2 diabetes,hyperglycemia, dyslipidemia, impaired glucose tolerance, metabolicsyndrome and/or cardiovascular disease.

WO2009068617 discloses PDE9 inhibiting compounds derived frompyrazolopyrimidinones with a substituted phenylmethyl- or pyridyl-methylgroup in the 6-position.

WO2010112437 discloses PDE9 inhibiting compounds derived frompyrazolopyrimidinones with a phenyl or heteroaryl substitutedarylmethyl- or heteroaryl-methyl group in the 6-position.

WO 2009/121919 discloses PDE9 inhibitors derived frompyrazolopyrimidinones with a non-aromatic heterocyclyl group in the1-position, among which is tetrahydropyranyl.

WO 2010/026214 discloses PDE9 inhibitors derived frompyrazolopyrimidinones with a cycloalkyl or a cycloalkenyl group in the1-position, among which is 4,4-difluorocyclohexyl.

Some prior art is directed to chemically nucleoside derivatives. Asexamples it is referred to WO 2002/057425, which discloses nucleosidederivatives, which are inhibitors of RNA-dependent RNA viral polymerase,or WO 2001/060315, which discloses nucleoside derivatives for thetreatment of hepatitis C infection or EP679657, which disclosescompounds that serve as ribonucleoside analogues or US2002058635, whichdiscloses purine L-nucleoside compounds, in which both the purine ringsand the carbohydrate ring (pentose ring) are either modified,functionalized, or both. So the carbohydrate ring for example must showat least one esterified hydroxy group.

WO 2005/051944 discloses oxetane-containing nucleosides, for thetreatment of nucleoside analogue related disorders such as disordersinvolving cellular proliferation and infection.

WO 2006/084281 discloses inhibitors of the E1 activation enzyme thathave a sulfonamide moiety.

WO 1998/40384 discloses pyrazolopyrimidinones which are PDE1, 2 and 5inhibitors and can be employed for the treatment of cardiovascular andcerebrovascular disorders and disorders of the urogenital system.

CH396 924, CH396 925, CH396 926, CH396 927, DE1147234, DE1149013,describe pyrazolopyrimidines which have a coronary-dilating effect andwhich can be employed for the treatment of disturbances of myocardialblood flow.

U.S. Pat. No. 3,732,225 describes pyrazolopyrimidines which have ananti-inflammatory and blood glucose-lowering effect.

DE2408906 describes styrylpyrazolopyrimidinones which can be employed asantimicrobial and anti-inflammatory agents for the treatment of, forexample, oedema.

OBJECTIVE OF THE INVENTION

Changes in the substitution pattern of pyrazolopyrimidinones result ininteresting changes concerning biological activity, respectively changesin the affinity towards different target enzymes.

Therefore it is an objective of the present invention to providecompounds as herein described, in particular in the claims, thateffectively modulate PDE9A for the purpose of the development of amedicament, in particular in view of diseases or conditions, thetreatment of which is accessible via PDE9A modulation.

It is another objective of the present invention to provide compoundsthat are useful for the manufacture of a medicament for the treatment ofCNS disorders.

Yet another objective of the present invention is to provide compoundswhich show a favourable safety profile.

Another objective of the present invention is to provide compounds thathave a favourable selectively profile in favour of PDE9A inhibition overother PDE family members and other pharmacological targets and by thismay provide an advantage.

Yet another objective is to provide a medicament that may not only servefor treatment but might also be used for the prevention or modificationof the corresponding disease or condition.

The present invention further provides a pharmaceutical compositioncomprising a compound as herein described, in particular in the claimsand a pharmaceutically acceptable carrier.

The present invention further provides a method for the treatment of anyof the conditions as described herein in a mammal in need of suchtreatment, preferably a human, comprising administering to the mammal atherapeutically effective amount of a compound as herein described, inparticular in the claims.

The present invention further provides a compound as herein described,in particular in the claims, for use in a method of treatment of thehuman or animal body by therapy.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

The compounds of the present invention are characterised by generalformula (I):

wherein

R¹: is a 5 or 6 membered heteroaryl-group whereby 1, 2, 3 or 4,preferably 1, 2 or 3, of the ring atoms are heteroatoms that areselected independently of each other from N, O or S,

-   -   whereby said 5 or 6 membered aromatic heteroaryl-group        optionally may be substituted by 1, 2, 3 or 4, preferably 1 or 2        substituents, whereby said substituents may be selected        independently of one another from the group consisting of        fluorine, chlorine, bromine, HO—, NC—, F₃C—, HF₂C—, FH₂C—,        methyl, H₂N— and (CH₃)₂N—;

R²: is selected from the group consisting of fluorine, NC—, F₃C—, HF₂C—,FH₂C— and methyl, preferably fluorine, NC—, F₃C— and methyl;

D: is selected from the group consisting of cyclopentyl, cyclohexyl,tetrahydrofuranyl, tetrahydropyranyl, 2-, 3- and 4-pyridyl,

-   -   whereby cyclopentyl and cyclohexyl optionally may be substituted        by 1 or 2 substituents, whereby said substituents may be        selected independently of one another from the group consisting        of fluorine, NC—, F₃C—, HF₂C— and FH₂C—;    -   whereby tetrahydrofuranyl and tetrahydropyranyl optionally may        be substituted by 1 or 2 substituents, whereby said substituents        may be selected independently of one another from the group        consisting of fluorine, NC—, F₃C—, HF₂C— and FH₂C—;    -   whereby pyridyl optionally may be substituted by 1, 2, 3 or 4        substituents, whereby said substituents may be selected        independently of one another from the group consisting of        fluorine, chlorine, bromine, NC—, F₃C—, HF₂C—, FH₂C—, F₃C—CH₂—,        C₁₋₆-alkyl- and C₃₋₇-cycloalkyl;

m: is selected from 1 or 2, preferably 1;

n: is selected from 0, 1 or 2, preferably, 0 or 1, more preferably 0,

-   -   whereby if n=2, these two groups R² are selected independently        of one another;

and salts, preferably pharmaceutically acceptable salts thereof,solvates thereof and the solvates of the aforementioned salts thereof;

with the proviso that the compound is not the followingoxadiazolyl-derivative

be it in the form of any possible stereoisomer or a mixture of all orsome thereof or salt thereof or solvate thereof or a solvate of a saltthereof.

This embodiment is embodiment 1 of the present invention.

Concerning the proviso definition above: it shall be understood thatthroughout this description this definition of the compound,specifically

-   -   “the following oxadiazolyl-derivative

-   -   be it in the form of any possible stereoisomer or a mixture of        all or some thereof”

encompasses the following stereoisomers beside the mixtures of thesecompounds:

Embodiment 2 of the present invention: Another embodiment of theinvention concerns a compound according to general formula (I), wherein

R¹: is a 5 or 6 membered heteroaryl-group whereby 1, 2, 3 or 4,preferably 1, 2 or 3, of the ring atoms are heteroatoms that areselected independently of each other from N, O or S,

-   -   whereby said 5 or 6 membered aromatic heteroaryl-group        optionally may be substituted by 1, 2, 3 or 4, preferably 1 or 2        substituents, whereby said substituents may be selected        independently of one another from the group consisting of        fluorine, chlorine, bromine, NC—, F₃C—, HF₂C—, FH₂C—, methyl,        H₂N— and (CH₃)₂N—;

R²: is selected from the group consisting of fluorine, NC—, F₃C—, HF₂C—,FH₂C— and methyl, preferably fluorine, NC—, F₃C— and methyl;

D: is selected from the group consisting of cyclopentyl, cyclohexyl,tetrahydrofuranyl, tetrahydropyranyl, 2-, 3- and 4-pyridyl,

-   -   whereby cyclopentyl and cyclohexyl optionally may be substituted        by 1 or 2 substituents, whereby said substituents may be        selected independently of one another from the group consisting        of fluorine, F₃C—, HF₂C— and FH₂C—;    -   whereby tetrahydrofuranyl and tetrahydropyranyl optionally may        be substituted by 1 or 2 substituents, whereby said substituents        may be selected independently of one another from the group        consisting of fluorine, F₃C—, HF₂C— and FH₂C—;    -   whereby pyridyl optionally may be substituted by 1, 2, 3 or 4,        preferably 1, 2 or 3, more preferably 1 or 2, substituents,        whereby said substituents may be selected independently of one        another from the group consisting of fluorine, chlorine,        bromine, NC—, F₃C—, HF₂C—, FH₂C—, F₃C—CH₂—, C₁₋₆-alkyl- and        C₃₋₇-cycloalkyl;

m: is selected from 1 or 2, preferably m is 1;

n: is selected from the group consisting 0, 1 or 2, preferably n is 0 or1, more preferably n is 0,

-   -   whereby if n=2, these two groups R² are selected independently        of one another;

and salts, preferably pharmaceutically acceptable salts thereof,solvates thereof and the solvates of the aforementioned salts thereof;

with the proviso that the compound is not the followingoxadiazolyl-derivative

be it in the form of any possible stereoisomer or a mixture of all orsome thereof or salt thereof or solvate thereof or a solvate of a saltthereof.

Embodiment 3 of the present invention: Another embodiment of theinvention concerns a compound according to general formula (I), wherein

R¹: is a 5 membered heteroaryl-group whereby 1, 2, 3 or 4, preferably 1,2 or 3, more preferably 2 or 3 of the ring atoms are heteroatoms thatare selected independently of each other from N, O or S,

-   -   whereby said 5 membered aromatic heteroaryl-group optionally may        be substituted by 1, 2, 3 or 4, preferably 1 or 2 substituents,        whereby said substituents may be selected independently of one        another from the group consisting of fluorine, chlorine,        bromine, NC—, F₃C—, HF₂C—, FH₂C—, methyl, H₂N— and (CH₃)₂N—;

R²: is selected from the group consisting of fluorine, NC—, F₃C—, HF₂C—,FH₂C— and methyl, preferably fluorine, NC—, F₃C— and methyl;

D: is selected from the group consisting of cyclopentyl, cyclohexyl,tetrahydrofuranyl, tetrahydropyranyl, 2-, 3- and 4-pyridyl,

-   -   whereby cyclopentyl and cyclohexyl optionally may be substituted        by 1 or 2 substituents, whereby said substituents may be        selected independently of one another from the group consisting        of fluorine, F₃C—, HF₂C— and FH₂C—;    -   whereby tetrahydrofuranyl and tetrahydropyranyl optionally may        be substituted by 1 or 2 substituents, whereby said substituents        may be selected independently of one another from the group        consisting of fluorine, F₃C—, HF₂C— and FH₂C—;    -   whereby pyridyl optionally may be substituted by 1, 2, 3 or 4,        preferably 1, 2 or 3, more preferably 1 or 2, substituents,        whereby said substituents may be selected independently of one        another from the group consisting of fluorine, chlorine,        bromine, NC—, F₃C—, HF₂C—, FH₂C—, F₃C—CH₂—, C₁₋₆-alkyl- and        C₃₋₇-cycloalkyl;

m: is selected from 1 or 2, preferably m is 1;

n: is selected from 0, 1 or 2, preferably n is 0 or 1, more preferably nis 0,

-   -   whereby if n=2, these two groups R² are selected independently        of one another;

and salts, preferably pharmaceutically acceptable salts thereof,solvates thereof and the solvates of the aforementioned salts thereof;

with the proviso that the compound is not the followingoxadiazolyl-derivative

be it in the form of any possible stereoisomer or a mixture of all orsome thereof or salt thereof or solvate thereof or a solvate of a saltthereof.

Embodiment 4 of the present invention: Another embodiment of theinvention concerns a compound according to general formula (I), wherein

R¹: is a 6 membered heteroaryl-group whereby 1, 2, 3 or 4, preferably 1,2 or 3, more preferably 2 or 3 of the ring atoms are heteroatoms thatare selected independently of each other from N, O or S,

-   -   whereby said 6 membered aromatic heteroaryl-group optionally may        be substituted by 1, 2, 3 or 4, preferably 1 or 2 substituents,        whereby said substituents may be selected independently of one        another from the group consisting of fluorine, chlorine,        bromine, NC—, F₃C—, HF₂C—, FH₂C—, methyl, H₂N— and (CH₃)₂N—;

R²: is selected from the group consisting of fluorine, NC—, F₃C—, HF₂C—,FH₂C— and methyl, preferably fluorine, NC—, F₃C— and methyl;

D: is selected from the group consisting of cyclopentyl, cyclohexyl,tetrahydrofuranyl, tetrahydropyranyl, 2-, 3- and 4-pyridyl,

-   -   whereby cyclopentyl and cyclohexyl optionally may be substituted        by 1 or 2 substituents, whereby said substituents may be        selected independently of one another from the group consisting        of fluorine, F₃C—, HF₂C— and FH₂C—;    -   whereby tetrahydrofuranyl and tetrahydropyranyl optionally may        be substituted by 1 or 2 substituents, whereby said substituents        may be selected independently of one another from the group        consisting of fluorine, F₃C—, HF₂C— and FH₂C—;    -   whereby pyridyl optionally may be substituted by 1, 2, 3 or 4,        preferably 1, 2 or 3, more preferably 1 or 2, substituents,        whereby said substituents may be selected independently of one        another from the group consisting of fluorine, chlorine,        bromine, NC—, F₃C—, HF₂C—, FH₂C—, F₃C—CH₂—, C₁₋₆-alkyl- and        C₃₋₇-cycloalkyl;

m: is selected from 1 or 2, preferably m is 1;

n: is selected from 0, 1 or 2, preferably n is 0 or 1, more preferably nis 0,

-   -   whereby if n=2, these two groups R² are selected independently        of one another;

and salts, preferably pharmaceutically acceptable salts thereof,solvates thereof and the solvates of the aforementioned salts thereof.

Embodiment 5 of the present invention: Another embodiment of theinvention concerns a compound according to general formula (I), wherein

R¹: is a heteroaryl-group selected from the group consisting ofthiadiazolyl, oxadiazolyl, isoxazolyl, thiazolyl, oxazolyl, pyridyl andpyrimidinyl, preferably said heteroaryl-group being selected from thegroup consisting of thiadiazolyl, oxadiazolyl, isoxazolyl, thiazolyl,oxazolyl and pyrimidinyl,

-   -   whereby said heteroaryl-group optionally may be substituted by        1, 2, 3 or 4, preferably 1 or 2 substituents, whereby said        substituents may be selected independently of one another from        the group consisting of fluorine, chlorine, bromine, NC—, F₃C—,        HF₂C—, FH₂C—, methyl, H₂N— and (CH₃)₂N—;

R²: is selected from the group consisting of fluorine, NC—, F₃C—, HF₂C—,FH₂C— and methyl, preferably fluorine, NC—, F₃C— and methyl;

D: is selected from the group consisting of cyclopentyl, cyclohexyl,tetrahydrofuranyl, tetrahydropyranyl, 2-, 3- and 4-pyridyl,

-   -   whereby cyclopentyl and cyclohexyl optionally may be substituted        by 1 or 2 substituents, whereby said substituents may be        selected independently of one another from the group consisting        of fluorine, F₃C—, HF₂C— and FH₂C—;    -   whereby tetrahydrofuranyl and tetrahydropyranyl optionally may        be substituted by 1 or 2 substituents, whereby said substituents        may be selected independently of one another from the group        consisting of fluorine, F₃C—, HF₂C— and FH₂C—;    -   whereby pyridyl optionally may be substituted by 1, 2, 3 or 4,        preferably 1, 2 or 3, more preferably 1 or 2, substituents,        whereby said substituents may be selected independently of one        another from the group consisting of fluorine, chlorine,        bromine, NC—, F₃C—, HF₂C—, FH₂C—, F₃C—CH₂—, C₁₋₆-alkyl- and        C₃₋₇-cycloalkyl;

m: is selected from 1 or 2, preferably m is 1;

n: is selected from 0, 1 or 2, preferably n is 0 or 1, more preferably nis 0,

-   -   whereby if n=2, these two groups R² are selected independently        of one another;

and salts, preferably pharmaceutically acceptable salts thereof,solvates thereof and the solvates of the aforementioned salts thereof;

with the proviso that the compound is not the followingoxadiazolyl-derivative

be it in the form of any possible stereoisomer or a mixture of all orsome thereof or salt thereof or solvate thereof or a solvate of a saltthereof.

Embodiment 6 of the present invention: Another embodiment of theinvention concerns a compound according to general formula (I), wherein

R¹: is a heteroaryl-group selected from the group consisting ofthiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl,isoxazolyl, thiazolyl, oxazolyl, pyridyl and pyrimidinyl, preferablysaid heteroaryl-group being selected from the group consisting ofthiadiazolyl, isoxazolyl, thiazolyl, oxazolyl, pyridyl and pyrimidinyl,

-   -   whereby said heteroaryl-group optionally may be substituted by        1, 2, 3 or 4, preferably 1 or 2 substituents, whereby said        substituents may be selected independently of one another from        the group consisting of fluorine, chlorine, bromine, NC—, F₃C—,        HF₂C—, FH₂C—, methyl, H₂N— and (CH₃)₂N—;

R²: is selected from the group consisting of fluorine, NC—, F₃C—, HF₂C—,FH₂C— and methyl, preferably fluorine, NC—, F₃C— and methyl;

D: is selected from the group consisting of cyclopentyl, cyclohexyl,tetrahydrofuranyl, tetrahydropyranyl, 2-, 3- and 4-pyridyl,

-   -   whereby cyclopentyl and cyclohexyl optionally may be substituted        by 1 or 2 substituents selected from the group consisting of        fluorine, F₃C—, HF₂C— and FH₂C—;    -   whereby tetrahydrofuranyl and tetrahydropyranyl optionally may        be substituted independently of one another by 1 or 2        substituents, whereby said substituents may be selected        independently of one another from the group consisting of        fluorine, F₃C—, HF₂C— and FH₂C—;    -   whereby pyridyl optionally may be substituted by 1, 2, 3 or 4,        preferably 1, 2 or 3, more preferably 1 or 2, substituents,        whereby said substituents may be selected independently of one        another from the group consisting of fluorine, chlorine,        bromine, NC—, F₃C—, HF₂C—, FH₂C—, F₃C—CH₂—, C₁₋₆-alkyl- and        C₃₋₇-cycloalkyl;

m: is selected from 1 or 2, preferably m is 1;

n: is selected from 0, 1 or 2, preferably n is 0 or 1, more preferably nis 0,

-   -   whereby if n=2, these two groups R² are selected independently        of one another;

and salts, preferably pharmaceutically acceptable salts thereof,solvates thereof and the solvates of the aforementioned salts thereof.

Embodiment 7 of the present invention: embodiment 7 of the inventionconcerns a compound that corresponds in all aspects with embodiment 6,except in that

R¹: is a heteroaryl-group selected from the group consisting ofthiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl,isoxazolyl, thiazolyl, oxazolyl and pyrimidinyl, preferably saidheteroaryl-group being selected from the group consisting ofthiadiazolyl, isoxazolyl, thiazolyl, oxazolyl and pyrimidinyl,

-   -   whereby said heteroaryl-group optionally may be substituted by        1, 2, 3 or 4, preferably 1 or 2 substituents, whereby said        substituents may be selected independently of one another from        the group consisting of fluorine, chlorine, bromine, NC—, F₃C—,        HF₂C—, FH₂C—, methyl, H₂N— and (CH₃)₂N—.

Embodiment 8 of the present invention: Another embodiment of theinvention concerns a compound according to general formula (I), wherein

R¹: is a heteroaryl-group selected from the group consisting of[1,3,4]thiadiazol-2-yl, isoxazol-5-yl, thiazol-5-yl-, oxazol-2-yl,pyridin-2-yl and pyrimidin-2-yl, preferably said heteroaryl-group beingselected from the group consisting of [1,3,4]thiadiazol-2-yl,isoxazol-5-yl, thiazol-5-yl-, oxazol-2-yl and pyrimidin-2-yl,

-   -   whereby said heteroaryl-group optionally may be substituted by 1        or 2 substituents,    -   whereby said substituents may be selected independently of one        another from the group consisting of fluorine, chlorine,        bromine, CN—, methyl and H₂N—;

R²: is selected from the group consisting of fluorine, NC—, F₃C—, HF₂C—,FH₂C— and methyl, preferably fluorine, NC—, F₃C— and methyl;

D: is selected from the group consisting of cyclopentyl, cyclohexyl,tetrahydrofuranyl, tetrahydropyranyl, 2-, 3- and 4-pyridyl

-   -   whereby cyclopentyl and cyclohexyl optionally may be substituted        by 1 or 2 substituents, whereby said substituents may be        selected independently of one another from the group consisting        of fluorine, F₃C—, HF₂C— and FH₂C—; preferably by fluorine;    -   whereby tetrahydrofuranyl and tetrahydropyranyl optionally may        be substituted by 1 or 2 substituents, whereby said substituents        may be selected independently of one another from the group        consisting of fluorine, F₃C—, HF₂C— and FH₂C—;    -   whereby pyridyl optionally may be substituted by 1, 2, 3 or 4,        preferably 1, 2 or 3, more preferably 1 or 2, substituents,        whereby said substituents may be selected independently of one        another from the group consisting of fluorine, chlorine,        bromine, NC—, F₃C—, HF₂C—, FH₂C—, F₃C—CH₂— and methyl;    -   whereby preferably D is selected from the group consisting of        4,4-difluorocyclohex-1-yl, tetrahydropyranyl, thereof preferably        tetrahydropyran-4-yl, and 4-methy-3-pyridyl;

m: is selected from 1 or 2, preferably m is 1;

n: is selected from 0, 1 or 2, preferably n is 0 or 1, more preferably nis 0,

-   -   whereby if n=2, these two groups R² are selected independently        of one another;

and salts, preferably pharmaceutically acceptable salts thereof,solvates thereof and the solvates of the aforementioned salts thereof.

Embodiments 9 to 16 of the Present Invention:

In any of the above mentioned embodiments 1 to 8 the preferred compoundsare represented by formula (II):

Compounds according to formula (II)

with

R¹: as defined in any of the aforementioned embodiments 1 to 8;

D being either 4,4-difluorocyclohexyl or tetrahydropyran-4-yl or4-methy-3-pyridyl and none of these two groups has further substituents;

and salts, preferably pharmaceutically acceptable salts thereof,solvates thereof and the solvates of the aforementioned salts thereof;

with the proviso that the compound is not the followingoxadiazolyl-derivative

be it in the form of any possible stereoisomer or a mixture of all orsome thereof or salt thereof or solvate thereof or a solvate of a saltthereof.

The preferred embodiments 9 to 16 according to formula (II) derive fromembodiments according to formula (I) in that:

m in formula (I) is 1, so that the corresponding cycloalkyl-group is acyclobutyl;

n in formula (I) is 0;

D in formula (I) is selected from the group of 4,4-difluorocyclohexyl(without further substituents, i.e. unsubstituted) andtetrahydropyran-4-yl (without further substituents, i.e. unsubstituted)and 4-methy-3-pyridyl;

R¹ in formula (I) is attached to said aforementioned cyclobutyl (m=1) inthe 2-position thereof while the 1 position of said cyclobutyl is theattachment point to the 6 position of the D-substitutedpyrazolopyrimidinone.

The corresponding embodiments are designated as embodiments 9, 10, 11,12, 13, 14, 15 and 16 respectively.

Embodiment 9 derives from embodiment 1, embodiment 10 from embodiment 2,embodiment 11 from embodiment 3, embodiment 12 from embodiment 4,embodiment 13 from embodiment 6, embodiment 14 from embodiment 6,embodiment 15 from embodiment 7, embodiment 16 from embodiment 7.

Embodiments 17 to 24 of the Present Invention:

Within each of the above mentioned embodiments 1 to 16 more preferredcompounds are represented by formula (II):

with

R¹: as defined in any of the aforementioned embodiments 1 to 8;

D being either 4,4-difluorocyclohexyl or tetrahydropyran-4-yl and noneof these two groups has further substituents;

and salts, preferably pharmaceutically acceptable salts thereof,solvates thereof and the solvates of the aforementioned salts thereof,

with the proviso that the compound is not the followingoxadiazolyl-derivative

be it in the form of any possible stereoisomer or a mixture of all orsome thereof or salt thereof or solvate thereof or a solvate of a saltthereof.

For all embodiments 1 to 24: the configuration of the cycloalkyl groupat position 6 of the pyrazolopyrimidinones group with respect to saidpyrazolopyrimidinones group and the substituent R¹ may be cis or trans.

In this respect the compounds of the invention may have the followingconfigurations:

whereby R¹, R², m, n and D are as defined in any of embodiments 1 to 8.

These stereochemically defined embodiments are a further aspect of theinvention.

Embodiment 25 of the Present Invention:

Within the context of the present invention one or more compound(s) is(are) preferred that are selected from the group of specifically definedspecies as listed in the following table. The left column contains aletter code to identify the compound family, which is the group ofcompounds that have the same general chemical structural formula if nostereochemical properties are considered. Members of these compoundfamilies are exemplified in the section Exemplary embodiments.

Table of species: A

Aa

Ab

Ac

Ad

B

Ba

Bb

Bc

Bd

C

Ca

Cb

Cc

Cd

D

Da

Db

Dc

Dd

E

Ea

Eb

Ec

Ed

F

Fa

Fb

Fc

Fd

G1

G1a

G1b

G1c

G1d

G2

G2a

G2b

G2c

G2d

H1

H1a

H1b

H1c

H1d

H2

H2a

H2b

H2c

H2d

I

Ia

Ib

Ic

Id

J

Ja

Jb

Jc

Jd

K

Ka

Kb

Kc

Kd

L

La

Lb

Lc

Ld

M

Ma

Mb

Mc

Md

N

Na

Nb

Nc

Nd

O

Oa

Ob

Oc

Od

P

Pa

Pb

Pc

Pd

Q

Qa

Qb

Qc

Qd

R

Ra

Rb

Rc

Rd

S

Sa

Sb

Sc

Sd

T

Ta

Tb

Tc

Td

and salts, preferably pharmaceutically acceptable salts thereof,solvates thereof and the solvates of the aforementioned salts thereof.

Within the latter group of compounds, compounds that show transconfiguration with respect to the substitution at the cyclobutyl-groupmay be preferred over compounds with cis configuration. Of the possibletrans configured compounds one thereof may show advantages in efficacy.The more efficacious a compound the more it is among the preferredcompounds.

Another criterion which may differentiate preferred compounds accordingto the invention is the balance of efficacy and safety, such as forexample selectivity vs. other PDE family members such as PDE1C.

For one pair of trans configured compounds according to the experimentalpart a single crystal X-ray structure analysis revealed that theabsolute stereochemistry of the compound which showed lower efficacythan its enantiomer is R,R. As a consequence thereof absolutestereochemistry of the compound with the higher efficacy is S,S.

For said compound the S,S-configuration is represented by the followingstructure according to general formula (II):

In analogy, one may assume that among the compounds according toembodiment 25, such compounds that show the same absolutestereochemistry might be the more active ones compared with the othermembers of the same compound family. According to the present invention,within the same compound family the more active compounds are preferredover the less active compounds. The compound family is the group ofcompounds that differ in their chemical structure only with regard tostereochemical properties.

The different stereoisomers are subject to individual embodimentsaccording to the invention:

embodiment 26 of the present invention concerns a compound according toany one of embodiments 1 to 25, whereby the compound shows the followingstereochemical properties

if the compound generally can be represented if the compound generallycan be represented by formula (I): by formula (II):

embodiment 27 of the present invention concerns a compound according toany one of embodiments 1 to 25, whereby the compound shows the followingstereochemical properties:

if the compound generally can be represented if the compound generallycan be represented by formula (I): by formula (II):

embodiment 28 of the present invention concerns a compound according toany one of embodiments 1 to 25, whereby the compound shows the followingstereochemical properties:

if the compound generally can be represented if the compound generallycan be represented by formula (I): by formula (II):

embodiment 29 of the present invention concerns a compound according toany one of embodiments 1 to 25, whereby the compound shows the followingstereochemical properties:

if the compound generally can be represented if the compound generallycan be represented by formula (I): by formula (II):

Embodiment 30 of the present invention: Another set of preferredembodiment of the present invention derives from each of theaforementioned embodiments concerning compounds according to formula (I)or (II), inclusively the preferences concerning stereochemicalproperties thereof, in that

R¹ being pyrimidinyl, or pyridyl, preferably pyrimidin-2-yl orpyrdin-2-yl,

m=1,

n=0 and

D is selected from the group consisting of cyclopentyl, cyclohexyl,tetrahydrofuranyl, tetrahydropyranyl, 2-, 3- and 4-pyridyl

-   -   whereby cyclopentyl and cyclohexyl optionally may be substituted        by 1 or 2 substituents, whereby said substituents may be        selected independently of one another from the group consisting        of fluorine, F₃C—, HF₂C— and FH₂C—; preferably by fluorine;    -   whereby tetrahydrofuranyl, tetrahydropyranyl optionally may be        substituted by 1 or 2 substituents, whereby said substituents        may be selected independently of one another from the group        consisting of fluorine, F₃C—, HF₂C— and FH₂C—;    -   whereby pyridyl optionally may be substituted by 1, 2, 3 or 4,        preferably 1, 2 or 3, more preferably 1 or 2, substituents,        whereby said substituents may be selected independently of one        another from the group consisting of fluorine, chlorine,        bromine, NC—, F₃C—, HF₂C—, FH₂C—, F₃C—CH₂— and methyl;    -   whereby preferably D is selected from the group consisting of        4,4-difluorocyclohex-1-yl, tetrahydropyranyl and        4-methy-3-pyridyl

and salts, preferably pharmaceutically acceptable salts thereof,solvates thereof and the solvates of the aforementioned salts thereof.

For each of the embodiments 1 to 30: whenever D may betetrahydrofuranyl, it is preferably tetrahydrofuran-3-yl; whenever D maybe tetrahydropyranyl it is preferable tetrahydropyran-3-yl ortetrahydropyran-4-yl, more preferably tetrahydropyran-4-yl.

For each of the embodiments 1 to 30: the heteroaryl-group R¹ preferablyis bound via a carbon ring atom thereof to the cycloalkyl-group that isattached to the 6-position of the pyrazolopyrimidinone-scaffold.According to general formula (I) said cycloalkyl-group may be acyclobutyl- or cyclopentyl-group, according to general formula (II) saidcycloalkyl-group is a cyclobutyl-group.

Terms and Definitions

Terms not specifically defined herein should be given the meanings thatwould be given to them by a person skilled in the art in light of thedisclosure and the context. Examples include that specific substituentsor atoms are presented with their 1 or 2 letter code, like H forhydrogen, N for nitrogen, C for carbon, O for oxygen, S for sulphur andthe like. Optionally but not mandatory the letter is followed by ahyphen to indicate a bond. As used in the specification, unlessspecified to the contrary, the following terms have the meaningindicated and the following conventions are adhered to.

In the groups, radicals, or moieties defined below, the number of carbonatoms is often specified preceding the group, for example, C₁₋₆ alkylmeans an alkyl group or alkyl radical having 1 to 6 carbon atoms. Ingeneral, for groups comprising two or more subgroups, the last namedgroup is the radical attachment point, for example, “(CH₃)₂N—” means amonovalent radical of the formula (CH₃)₂N—, which is attached via thenitrogen atom thereof (i.e. a dimethylamino-substituent). If the term ofa substituent starts or ends with a minus sign or hyphen, i.e.—, thissign emphasises the attachment point as in the aforementioned example(CH₃)₂N—, where the N is linked to the group of which thedimethylamino-group is a substituent. Unless otherwise specified below,conventional definitions of terms control and conventional stable atomvalences are presumed and achieved in all formulas and groups.

In general, if terms are specifically defined with a given context, suchspecific definitions shall prevail over the more general definitions asoutlined in this paragraph.

In general, all “tautomeric forms and isomeric forms and mixtures”,whether individual geometric isomers or optical isomers or racemic ornon-racemic mixtures of isomers, of a chemical structure or compound areintended, unless the specific stereochemistry or isomeric form isspecifically indicated in the compound name or structure. Specificdefinitions prevail.

“Substitution”: The term “substituted” as used herein explicitly orimplicitly, means that any one or more hydrogen(s) on the designatedatom is replaced with a member of the indicated group of substituents,provided that the designated atom's normal valence is not exceeded. Incase a substituent is bound via a double bond, e.g. an oxo substituent,such substituent replaces two hydrogen atoms on the designated atom. Thesubstitution shall result in a stable compound. “Stable” in this contextpreferably means a compound that from a pharmaceutical point of view ischemically and physically sufficiently stable in order to be used as anactive pharmaceutical ingredient of a pharmaceutical composition. If asubstituent is not defined, it shall be hydrogen. By the term“optionally substituted” is meant that either the corresponding group issubstituted or it is not. A characterisation that substituents of thesame group may be “selected independently of one another” shall mean,that the corresponding substituents may be the same or may be different.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

“pharmaceutically acceptable salt(s)” of the compounds according to theinvention are subject of the present invention as well. The term“pharmaceutically acceptable salt(s)” refers to derivatives of thedisclosed compounds wherein the parent compound is modified by makingacid or base salts thereof, preferably addition salts. Examples ofpharmaceutically acceptable salts include, but are not limited to,mineral or organic acid salts of basic residues/parts of the compoundsof the present invention such as aminofunctions; acidic residues/partswithin compounds of the present invention may form salts with alkali ororganic bases. The pharmaceutically acceptable salts include theconventional non-toxic salts or the quaternary ammonium salts of theparent compound formed, for example, from non-toxic inorganic or organicacids. For example, such conventional non-toxic salts include thosederived from inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid and thelike; and the salts prepared from organic acids such as acetic acid,propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid,malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid,maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid,benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid,fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid and the like.

Physiologically acceptable salts with bases also may include salts withconventional bases such as, by way of example and preferably, alkalimetal salts (e.g. sodium and potassium salts), alkaline earth metalsalts (e.g. calcium and magnesium salts) and ammonia, organic amineshaving 1 to 16 C atoms, such as, by way of example and preferably,ethylamine, diethylamine, triethylamine, ethyldiisopropylamine,monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine,dimethylaminoethanol, procaine, dibenzylamine, N-methyl-morpholine,dehydroabietylamine, arginine, lysine, ethylenediamine andmethylpiperidine and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound with basic or acidic properties byconventional chemical methods. Generally, such salts can be prepared byreacting the free acid or base form of these compounds with astoichiometric amount of the appropriate base or acid in water or in anorganic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred.

A “Prodrug” is considered a compound that is designed to release abiologically active compound according to the present invention in-vivowhen such prodrug is administered to a mammalian subject. Prodrugs ofcompounds according to the present invention are prepared by modifyingfunctional groups present in the compound of the invention in such a waythat these modifications are retransformed to the original functionalgroups under physiological conditions. It will be appreciated thatprodrugs of the compounds according to the present inventions aresubject to the present invention as well.

“Metabolites” are considered derivatives of the compounds according tothe present invention that are formed in-vivo. Active metabolites aresuch metabolites that cause a pharmacological effect. It will beappreciated that metabolites of the compounds according to the presentinventions are subject to the present invention as well, in particularactive metabolites.

Some of the compounds may form “solvates”. For the purposes of theinvention the term “solvates” refers to those forms of the compoundswhich form, in the solid or liquid state, a complex by coordination withsolvent molecules. Hydrates are a specific form of solvates in which thecoordination takes place with water. According to the present invention,the term preferably is used for solid solvates, such as amorphous ormore preferably crystalline solvates.

“Scaffold”: The scaffold of the compounds according to the presentinvention is represented by the following core structure. The numerationof the positions of the ring member atoms is indicated in bold:

It will be evident for the skilled person in the art, that this scaffoldcan be described by its tautomeric “enol” form

In the context of the present invention both structural representationsof the scaffold shall be considered the subject of the presentinvention, even if only one of the two representatives is presented.Without meant to be limiting or bound, it is believed that for themajority of compounds under ambient conditions and therewith underconditions which are the relevant conditions for a pharmaceuticalcomposition comprising said compounds, the equilibrium of the tautomericforms lies on the side of the pyrazolopyrimdin-4-one representation.Therefore, all embodiments are presented aspyrazolopyrimdin-4-one-derivatives or more precisely aspyrazolo[3,4-d]pyrimidin-4-one derivatives.

“Bonds”: If within a chemical formula of a ring system or a definedgroup, a substituent is directly linked to an atom or a group like “RyR”in the formula below, this shall mean that the substituent is onlyattached to the corresponding atom. If however from another substituentlike “RxR” a bond is not specifically linked to an atom of the ringsystem but drawn towards the center of the ring or group this means thatthis substituent “RxR” may be linked to any meaningful atom of the ringsystem/group unless stated otherwise.

The bond symbol “—” (=minus sign) or the symbol “—*” (=minus signfollowed by an asterisk sign) stands for the bond through which asubstituent is bound to the corresponding remaining part of themolecule/scaffold. In cases in that the minus sign does not seem to besufficiently clear, there may be added an asterisk to the bond symbol“—” in order to determine the point of attachment of said bond with thecorresponding main part of the molecule/scaffold.

The term “C₁₋₆-alkyl” denotes a saturated, branched or unbranchedhydrocarbon group with 1 to 6 C atoms. Examples of such groups includemethyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl,tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, tert-pentyl, n-hexyl,iso-hexyl. This definition applies for the use of “alkyl” in anyreasonable context within the present description in the absence of afurther definition.

The term “C₃₋₇-cycloalkyl” denotes a saturated monocyclic group with 3to 7 C ring atoms. Preferred are 5 or 6 membered cycloalkyl-groups.There are no other ring atoms than carbon atoms. Examples of such groupsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.This definition applies for “cycloalkyl” in any reasonable contextwithin the present description in the absence of a further definition.

The term “heteroaryl” used in this application denotes a heterocyclic,monocyclic aromatic ring system which includes within the ring systemitself in addition to at least one C atom one or more heteroatom(s)which are independently selected from N, O and/or S. Preferred areheteroaryls with 1 to 3 heteroatoms or 1 to 2 heteroatoms, or 1heteroatom. Preferred heteroatom is N.

The terms “pyridyl” defines a pyridine-substituent, sometimes alsocalled pyridinyl.

Expressions like “prevention”, “prophylaxis”, “prophylactic treatment”or “preventive treatment” used herein should be understood synonymousand in the sense that the risk to develop a condition mentionedhereinbefore is reduced, especially in a patient having elevated riskfor said conditions or a corresponding anamnesis. Thus the expression“prevention of a disease” as used herein means the management and careof an individual at risk of developing the disease prior to the clinicalonset of the disease. The purpose of prevention is to combat thedevelopment of the disease, condition or disorder and includes theadministration of the active compounds to prevent or delay the onset ofthe symptoms or complications and to prevent or delay the development ofrelated diseases, conditions or disorders. Success of said preventivetreatment is reflected statistically by reduced incidence of saidcondition within a patient population at risk for this condition incomparison to an equivalent patient population without preventivetreatment.

The expression “treatment” or “therapy” preferably means therapeutictreatment of (e.g. preferably human) patients having already developedone or more of said conditions in manifest, acute or chronic form,including symptomatic treatment in order to relieve symptoms of thespecific indication or causal treatment in order to reverse or partiallyreverse the condition or to delay the progression of the indication asfar as this may be possible, depending on the condition and the severitythereof. Thus the expression “treatment of a disease” as used hereinmeans the management and care of a patient having developed the disease,condition or disorder. The purpose of treatment is to combat thedisease, condition, disorder or a symptom thereof. Treatment includesthe administration of the active compounds to eliminate or control thedisease, condition or disorder as well as to alleviate the symptoms orcomplications associated with the disease, condition or disorder.

The following schemes shall illustrate generally how to manufacture thecompounds of the present invention by way of example. The abbreviatedsubstituents may be as defined for the embodiments of formula (I) if notdefined otherwise within the context of the schemes:

Scheme 1: In a first step 2-ethoxymethylene-malononitrile is condensedwith mono-substituted hydrazines by heating in an appropriate solventlike ethanol in the presence of a base (e.g. triethylamine) to form thecorresponding 5-amino-1H-pyrazole-4-carbonitriles. These compounds areconverted in a second step to the corresponding amides, e.g. bytreatment of an ethanolic solution with ammonia (25% in water) andhydrogen peroxide (35% in water). In a third step, heating withdicarboxylic acid diesters under basic conditions (e.g. sodium hydridein ethanol) followed by the addition of aqueous sodium hydroxide leadsto 4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl substitutedcarboxylic acids (path 1). The carboxylic acid functional group thereofis converted to a heteroaryl group as described in Scheme 2 yieldingpyrazolo[3,4-d]pyrimidin-4-ones as final products. Alternatively,4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl substituted nitrilescan be synthesized from dinitriles by heating under basic conditions(e.g. sodium hydride in ethanol) in the third step (path 2). The nitrilefunctional group is further converted to heteroaryl substituents asdescribed in Scheme 3 yielding pyrazolo[3,4-d]pyrimidin-4-ones as finalproducts. [cf., for example, A. Miyashita et al., Heterocycles 1990, 31,1309ff].

Scheme 2: 4-Oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl substitutedcarboxylic acids are treated under conditions listed in the table belowto form heteroaryl substituted pyrazolo[3,4-d]pyrimidin-4-ones as finalproducts. R^(a) is a substituent of R¹.

conditions as mentioned in scheme 2 R¹ R^(a) 1.) Reaction with HATU andDIPEA followed by a carboxylic acid hydrazide. 2.) Treatment withLawesson's reagent in THF at elevated temperatures.

H—, F₃C—, HF₂C—, FH₂C—, methyl 1.) Reaction with oxalylchloride in THFfollowed by treatment with trimethylsilydiazomethane followed byhydrochloric acid in dioxane. 2.) Reaction with a thioamide in EtOH.

H—, F₃C—, HF₂C—, FH₂C—, methyl 1.) Reaction with oxalylchloride in THFfollowed by treatment with trimethylsilydiazomethane followed byhydrochloric acid in dioxane. 2.) Reaction with a thiourea in EtOH.

H—, F₃C—, HF₂C—, FH₂C—, methyl 3.) Reaction with oxalylchloride in THFfollowed by treatment with trimethylsilydiazomethane and hydrochloricacid in dioxane. 4.) Reaction with a thiourea in EtOH.

H₂N—, (CH₃)₂N— 1.) Reaction with TBTU and DIPEA followed by a2-amino-alkohol. 2.) Oxidation with Dess-Martin- Periodinane indichloromethane. 3.) Treatment with Burgess-reagent in

H—, NC—, F₃C—, HF₂C—, FH₂C—, methyl DME at elevated temperatures. 1.)Reaction with TBTU and DIPEA followed by a 2-amino-ketone hydrochloride.2.) Treatment with Burgess-reagent in DME at elevated temperatures.

H—, NC—, F₃C—, HF₂C—, FH₂C—, methyl 1.) Reaction with TBTU and DIPEAfollowed by a 2-amino-alkohol. 2.) Oxidation with Dess-Martin-Periodinane in dichloromethane. 3.) Treatment with Lawesson's reagent in

H—, NC—, F₃C—, HF₂C—, FH₂C—, methyl THF at elevated temperatures. 1.)Reaction with TBTU and DIPEA followed by a 2-amino-ketone hydrochloride.2.) Treatment with Lawesson's reagent in THF at elevated temperatures.

H—, NC—, F₃C—, HF₂C—, FH₂C—, methyl 1.) Reaction with TBTU and DIPEAfollowed by 1,2-dimethyl- hydroxylamine hydrochloride. 2.) Reaction witha mixture prepared separately from propan-2-one oxime andn-buthyllithium followed by

— treatment with sulfuric acid in THF/ water. 1.) Reaction with TBTU andDIPEA followed by hydrazine hydrate. 2.) Treatment with triethoxymethaneat elevated temperatures.

—

Scheme 3: 4-Oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl substitutednitriles are mixed with methanol and treated with acetylchloride or,alternatively, mixed with a saturated solution of hydrochloric acid inethanol. The intermediates are treated in a second step with a solutionof ammonia in methanol to form the corresponding amidines. Reaction witha 1,1,3,3-tetraalkoxypropane yields pyrimidin-2-yl substitutedpyrazolo[3,4-d]pyrimidin-4-ones as final products.

Further alternative processes for preparingpyrazolo[3,4-d]pyrimidin-4-ones are known in the art and can likewise beemployed for synthesizing the compounds of the invention (see, forexample: P. Schmidt et al., Helvetica Chimica Acta 1962, 189, 1620ff.).

Scheme 4: The mono-substituted hydrazine derivatives, that are used instep 1 of scheme 1 can be prepared by reductive amination of a ketonewith hydrazinecarboxylic acid tert-butyl ester followed by adeprotection step as shown in scheme 4 for an D being cyclopentyl orcyclohexyl as defined in general formula (I) [cf., for example, J. W.Timberlake et al., “Chemistry of Hydrazo-, Azo-and Azoxy Groups”; Patai,S., Ed.; 1975, Chapter 4; S. C. Hung et al., Journal of OrganicChemistry 1981, 46, 5413-5414].

Scheme 5: As described in scheme 1, in a first step2-ethoxymethylene-malononitrile is condensed with mono-substitutedhydrazines by heating in an appropriate solvent like ethanol in thepresence of a base (e.g. triethylamine) to form the corresponding5-amino-1H-pyrazole-4-carbonitriles. These compounds are converted in asecond step to the corresponding amides, e.g. by treatment of anethanolic solution with ammonia (25% in water) and hydrogen peroxide(35% in water). In a third step, heating with R1 and R2 substitutedcyclobutyl or cyclopentyl carboxylic acid ester under basic conditions(e.g. sodium hydride in ethanol) leads to the finalpyrazolo[3,4-d]pyrimidin-4-ones as final products. [cf., for example, A.Miyashita et al., Heterocycles 1990, 31, 1309ff]. This procedure isdescribed in more detail for R¹ being pyridinyl, m being 1 and n being 0in the experimental section (examples 29 to 32).

Further information also can be found in:

-   -   WO 2004/099210 (in particular page 9, last paragraph to page 14,        line 8, incorporated by reference),    -   with respect to the general manufacture of compounds with D        being tetrahydropyranyl more information can be found in        WO2009/121919, particularly on page 120 to 125 and the        experimental part thereof (herewith incorporated by reference),    -   with respect to D being 4,4-difluorocyclohexyl more information        can be found in WO 2010/026214, particularly on page 59 to 63        and the experimental part thereof (herewith incorporated by        reference),    -   and in the experimental part (exemplary embodiments) of this        description. The letter in particular with respect to the        manufacture of the two building blocks:

Method of Treatment

The present invention refers to compounds, which are consideredeffective in the treatment of diseases. The compounds according to theinvention are effective and selective inhibitors of phosphodiesterase 9Aand can be used for the development of medicaments. Such medicamentsshall preferably be used for the treatment of diseases in which theinhibition of PDE9A can provide a therapeutic, prophylactic or diseasemodifying effect. Preferably the medicaments shall be used to improveperception, concentration, cognition, learning or memory, like thoseoccurring in particular in situations/diseases/syndromes such as: mildcognitive impairment, age-associated learning and memory impairments,age-associated memory losses, vascular dementia, craniocerebral trauma,stroke, dementia occurring after strokes (post stroke dementia),post-traumatic dementia, general concentration impairments,concentration impairments in children with learning and memory problems,Alzheimer's disease, Lewy body dementia, dementia with degeneration ofthe frontal lobes, including Picks syndrome, Parkinson's disease,progressive nuclear palsy, dementia with corticobasal degeneration,amyotropic lateral sclerosis (ALS), Huntington's disease, multiplesclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, HIVdementia, epilepsy, temporal lobe epilepsy, schizophrenia, schizophrenia(with dementia), Korsakoff's psychosis or cognitive impairmentassociated with depression or bipolar disorder.

Another aspect of the present invention may concern the treatment of adisease which is accessible by PDE9A modulation, in particular sleepdisorders like insomnia or narcolepsy, bipolar disorder, metabolicsyndrome, obesity, diabetes mellitus, including type 1 or type 2diabetes, hyperglycemia, dyslipidemia, impaired glucose tolerance, or adisease of the testes, brain, small intestine, skeletal muscle, heart,lung, thymus or spleen.

Thus the medical aspect of the present invention can be summarised inthat it is considered that a compound according to formula (I) or (II)as herein defined, in particular the specifically defined speciescompounds is used as a medicament.

Such a medicament preferably is for the treatment of a CNS disease.

In an alternative use, the medicament is for the treatment of a CNSdisease, the treatment of which is accessible by the inhibition of PDE9.

In an alternative use, the medicament is for the treatment of a diseasethat is accessible by the inhibition of PDE9, specifically PDE9A.

In the most preferred alternative use, the medicament is for thetreatment, amelioration and/or prevention of cognitive impairment beingrelated to perception, concentration, cognition, learning or memory,preferably if such cognitive impairment is associated with a disease orcondition as described in this section.

In an alternative use, the medicament is for the treatment ameliorationand/or prevention of cognitive impairment being related toage-associated learning and memory impairments, age-associated memorylosses, vascular dementia, craniocerebral trauma, stroke, dementiaoccurring after strokes (post stroke dementia), post-traumatic dementia,general concentration impairments, concentration impairments in childrenwith learning and memory problems, Alzheimer's disease, Lewy bodydementia, dementia with degeneration of the frontal lobes, includingPicks syndrome, Parkinson's disease, progressive nuclear palsy, dementiawith corticobasal degeneration, amyotropic lateral sclerosis (ALS),Huntington's disease, multiple sclerosis, thalamic degeneration,Creutzfeld-Jacob dementia, HIV dementia, epilepsy, temporal lobeepilepsy, schizophrenia, schizophrenia (with dementia), Korsakoff'spsychosis or cognitive impairment associated with depression or bipolardisorder.

In an alternative use, the medicament is for the treatment ofAlzheimer's disease, schizophrenia or cognitive impairment associatedwith Alzheimers's disease or associated with schizophrenia.

In an alternative use, the medicament is for the treatment of sleepdisorders, bipolar disorder, metabolic syndrome, obesity, diabetesmellitus, hyperglycemia, dyslipidemia, impaired glucose tolerance, or adisease of the testes, brain, small intestine, skeletal muscle, heart,lung, thymus or spleen.

In a further aspect of the invention, the present invention relates tothe method of treatment or prevention of a condition or disease selectedfrom the above listed groups of conditions and diseases, whereby themethod comprises the administration of a therapeutically effectiveamount of a compound according to the invention in a human being in needthereof.

Pharmaceutical Compositions

Medicaments for administration, which are also subject to the presentinvention, comprise a compound according to the present invention in atherapeutically effective amount and a pharmaceutical carrier. By“therapeutically effective amount” it is meant that if the medicament isapplied via the appropriate regimen adapted to the patient's condition,the amount of said compound of formula (I) will be sufficient toeffectively treat, to prevent or to decelerate the progression of thecorresponding disease, or otherwise to ameliorate the state of a patientsuffering from such a disease. It may be the case that the“therapeutically effective amount” in a mono-therapy will differ fromthe “therapeutically effective amount” in a combination therapy withanother medicament.

The dose range of the compounds of general formula (I) applicable perday may be usually from 0.1 to 5000 mg, preferably from 0.1 to 1000 mg,preferably from 2 to 500 mg, more preferably from 5 to 250 mg, mostpreferably from 10 to 100 mg. A dosage unit (e.g. a tablet) preferablymay contain between 2 and 250 mg, particularly preferably between 10 and100 mg of the compounds according to the invention.

The actual pharmaceutically effective amount or therapeutic dosage willdepend on factors known by those skilled in the art such as age, weight,gender or other condition of the patient, route of administration,severity of disease and the like.

The compounds according to the invention may be administered by oral,parenteral (intravenous, intramuscular etc.), intranasal, sublingual,inhalative, intrathecal, topical or rectal route. Suitable preparationsfor administering the compounds according to the present inventioninclude for example patches, tablets, capsules, pills, pellets, dragees,powders, troches, suppositories, liquid preparations such as solutions,suspensions, emulsions, drops, syrups, elixirs, or gaseous preparationssuch as aerosols, sprays and the like. The content of thepharmaceutically active compound(s) should be in the range from 0.05 to90 wt.-%, preferably 0.1 to 50 wt.-% of the composition as a whole.Suitable tablets may be obtained, for example, by mixing the activesubstance(s) with known excipients, for example inert diluents such ascalcium carbonate, calcium phosphate or lactose, disintegrants such ascorn starch or alginic acid, binders such as starch or gelatine,lubricants such as magnesium stearate or talc and/or agents for delayingrelease, such as carboxymethyl cellulose, cellulose acetate phthalate,or polyvinyl acetate. The tablets may also comprise several layers.

Coated tablets may be prepared accordingly by coating cores producedanalogously to the tablets with substances normally used for tabletcoatings, for example collidone or shellac, gum arabic, talc, titaniumdioxide or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number of layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

Syrups or elixirs containing the active substances or combinationsthereof according to the invention may additionally contain a sweetenersuch as saccharine, cyclamate, glycerol or sugar and a flavour enhancer,e.g. a flavouring such as vanillin or orange extract. They may alsocontain suspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents such as, for example, condensation products offatty alcohols with ethylene oxide, or preservatives such asp-hydroxybenzoates.

Solutions may be prepared in the usual way, e.g. with the addition ofisotonic agents, preservatives such as p-hydroxybenzoates or stabiliserssuch as alkali metal salts of ethylene-diamine-tetra-acetic acid,optionally using emulsifiers and/or dispersants, while if water shall beused as diluent, for example, organic solvents may optionally be used assolubilisers or dissolving aids and the solutions may be transferredinto injection vials or ampoules or infusion bottles.

Capsules containing one or more active substances or combinations ofactive substances may for example be prepared by mixing the activesubstances with inert carriers such as lactose or sorbitol and packingthem into gelatine capsules.

Suitable suppositories may be made for example by mixing with carriersprovided for this purpose, such as neutral fats or polyethyleneglycol orthe derivatives thereof.

Excipients which may be used include, for example, water,pharmaceutically acceptable organic solvents such as paraffins (e.g.petroleum fractions), vegetable oils (e.g. groundnut or sesame oil),mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carrierssuch as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk),synthetic mineral powders (e.g. highly dispersed silicic acid andsilicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers(e.g. lignin, spent sulphite liquors, methylcellulose, starch andpolyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc,stearic acid and sodium lauryl sulphate).

For oral use the tablets may contain, in addition to the carriersspecified, additives such as sodium citrate, calcium carbonate anddicalcium phosphate together with various additional substances such asstarch, preferably potato starch, gelatine and the like. Lubricants suchas magnesium stearate, sodium laurylsulphate and talc may also be usedto produce the tablets. In the case of aqueous suspensions the activesubstances may be combined with various flavour enhancers or colouringsin addition to the abovementioned excipients.

The dosage of the compounds according to the invention is naturallyhighly dependent on the method of administration and the complaint whichis being treated.

Combinations with Other Active Substances In another aspect the presentinvention relates to a combination therapy in which a compound accordingto the present invention is administered together with another activecompound. Accordingly, the invention also refers to pharmaceuticalformulations that provide such a combination of active ingredients,whereby one of which is a compound of the present invention. Suchcombinations may be fixed dose combinations (the active ingredients thatare to be combined are subject of the same pharmaceutical formulation)or free dose combinations (active ingredients are in separatepharmaceutical formulations).

Consequently, a further aspect of the present invention refers to acombination of each of the compounds of the present invention,preferably at least one compound according to the present invention,with another active compound for example selected from the group ofbeta-secretase inhibitors; gamma-secretase inhibitors; gamma-secretasemodulators; amyloid aggregation inhibitors such as e.g. alzhemed;directly or indirectly acting neuroprotective and/or disease-modifyingsubstances; anti-oxidants, such as e.g. vitamin E , ginko biloba orginkolide; anti-inflammatory substances, such as e.g. Cox inhibitors,NSAIDs additionally or exclusively having AB (Abeta) loweringproperties; HMG-CoA reductase inhibitors, such as statins; acetylcholineesterase inhibitors, such as donepezil, rivastigmine, tacrine,galantamine; NMDA receptor antagonists such as e.g. memantine; AMPAreceptor agonists; AMPA receptor positive modulators, AMPkines, glycinetransporter 1 inhibitors; monoamine receptor reuptake inhibitors;substances modulating the concentration or release of neurotransmitters;substances inducing the secretion of growth hormone such as ibutamorenmesylate and capromorelin; CB-1 receptor antagonists or inverseagonists; antibiotics such as minocyclin or rifampicin; PDE1, PDE2,PDE4, PDE5 and/or PDE10 inhibitors, GABAA receptor inverse agonists;GABAA alpha5 receptor inverse agonists; GABAA receptor antagonists;nicotinic receptor agonists or partial agonists or positive modulators;alpha4beta2 nicotinic receptor agonists or partial agonists or positivemodulators; alpha7 nicotinic receptor agonists or partial agonists;histamine receptor H3 antagonists; 5-HT4 receptor agonists or partialagonists; 5-HT6 receptor antagonists; alpha2-adrenoreceptor antagonists,calcium antagonists; muscarinic receptor M1 agonists or partial agonistsor positive modulators; muscarinic receptor M2 antagonists; muscarinicreceptor M4 antagonists; metabotropic glutamate receptor 5 positiveallosteric modulators; metabotropic glutamate receptor 2 antagonists;metabotropic glutamate receptor 2/3 agonists; metabotropic glutamatereceptor 2 positive allosteric modulators and other substances thatmodulate receptors or enzymes in a manner such that the efficacy and/orsafety of the compounds according to the invention is increased and/orunwanted side effects are reduced.

This invention further relates to pharmaceutical compositions containingone or more, preferably one active substance. At least one activesubstance is selected from the compounds according to the inventionand/or the corresponding salts thereof. Preferably the compositioncomprises only one such active compound. In case of more than one activecompound the other one can be selected from the aforementioned group ofcombination partners such as alzhemed, vitamin E, ginkolide, donepezil,rivastigmine, tacrine, galantamine, memantine, ibutamoren mesylate,capromorelin, minocyclin and/or rifampicin. Optionally the compositioncomprises further ingredients such as inert carriers and/or diluents.

The compounds according to the invention may also be used in combinationwith immunotherapies such as e.g. active immunisation with Abeta orparts thereof or passive immunisation with humanised anti-Abetaantibodies or antibody fragments for the treatment of the abovementioned diseases and conditions.

The compounds according to the invention also may be combined withDimebon.

The compounds according to the invention also may be combined withantidepressants like amitriptyline imipramine hydrochloride (TOFRANIL),imipramine maleate (SURMONTIL), lofepramine, desipramine (NORPRAMIN),doxepin (SINEQUAN, ZONALON), trimipramine (SURMONTIL).

Or the compounds according to the invention also may be combined withserotonin (5-HT) reuptake inhibitors such as alaproclate, citalopram(CELEXA, CIPRAMIL) escitalopram (LEXAPRO, CIPRALEX), clomipramine(ANAFRANIL), duloxetine (CYMBALTA), femoxetine (MALEXIL), fenfluramine(PONDIMIN), norfenfluramine, fluoxetine (PROZAC), fluvoxamine (LUVOX),indalpine, milnacipran (IXEL), paroxetine (PAXIL, SEROXAT), sertraline(ZOLOFT, LUSTRAL), trazodone (DESYREL, MOLIPAXIN), venlafaxine(EFFEXOR), zimelidine (NORMUD, ZELMID), bicifadine, desvenlafaxine(PRISTIQ), brasofensme and tesofensine.

The combinations according to the present invention may be providedsimultaneously in one and the same dosage form, i.e. in form of acombination preparation, for example the two components may beincorporated in one tablet, e. g. in different layers of said tablet.The combination may be also provided separately, in form of a freecombination, i.e. the compounds of the present invention are provided inone dosage form and one or more of the above mentioned combinationpartners is provided in another dosage form. These two dosage forms maybe equal dosage forms, for example a co-administration of two tablets,one containing a therapeutically effective amount of the compound of thepresent invention and one containing a therapeutically effective amountof the above mentioned combination partner. It is also possible tocombine different administration forms, if desired. Any type of suitableadministration forms may be provided.

The compound according to the invention, or a physiologically acceptablesalt thereof, in combination with another active substance may be usedsimultaneously or at staggered times, but particularly close together intime. If administered simultaneously, the two active substances aregiven to the patient together; if administered at staggered times thetwo active substances are given to the patient successively within aperiod of less than or equal to 12, particularly less than or equal to 6hours.

The dosage or administration forms are not limited, in the context ofthe present invention any suitable dosage form may be used. For example,the dosage forms may be selected from solid preparations such aspatches, tablets, capsules, pills, pellets, dragees, powders, troches,suppositories, liquid preparations such as solutions, suspensions,emulsions, drops, syrups, elixirs, or gaseous preparations such asaerosols, sprays and the like.

The dosage forms are advantageously formulated in dosage units, eachdosage unit being adapted to supply a single dose of each activecomponent being present. Depending from the administration route anddosage form the ingredients are selected accordingly.

The dosage for the above-mentioned combination partners may beexpediently 1/5 of the normally recommended lowest dose up to 1/1 of thenormally recommended dose.

The dosage forms are administered to the patient for example 1, 2, 3, or4 times daily depending on the nature of the formulation. In case ofretarding or extended release formulations or other pharmaceuticalformulations, the same may be applied differently (e.g. once weekly ormonthly etc.). It is preferred that the compounds of the invention beadministered either three or fewer times, more preferably once or twicedaily.

EXAMPLES

Pharmaceutical Compositions

Examples which might illustrate possible pharmaceutical formulations,without being meant to be limiting:

The term “active substance” denotes one or more compounds according tothe invention including the salts thereof. In the case of one of theaforementioned combinations with one or more other active substances theterm “active substance” may also include the additional activesubstances.

Example A

Tablets Containing 100 mg of Active Substance

Composition: Tablet

active substance 100.0 mg lactose  80.0 mg corn starch  34.0 mgpolyvinylpyrrolidone  4.0 mg magnesium stearate  2.0 mg 220.0 mg

Example B

Tablets Containing 150 mg of Active Substance

Composition: Tablet

active substance 150.0 mg‘ powdered lactose 89.0 mg corn starch 40.0 mgcolloidal silica 10.0 mg polyvinylpyrrolidone 10.0 mg magnesium stearate 1.0 mg 300.0 mg 

Example C

Hard Gelatine Capsules Containing 150 mg of Active Substance

active substance 150.0 mg lactose  87.0 mg corn starch (dried)  80.0 mgmagnesium stearate  3.0 mg 320.0 mg

Example D

Composition: Suppository

active substance 150.0 mg polyethyleneglycol 1500 550.0 mgpolyethyleneglycol 6000 460.0 mg polyoxyethylene sorbitan 840.0 mgmonostearate 2000.0 mg 

Example E

Composition: Ampoules Containing 10 mg Active Substance

active substance 10.0 mg 0.01N hydrochloric acid q.s. double-distilledwater ad 2.0 mL

Example F

Composition: Ampoules Containing 50 mg of Active Substance

active substance 50.0 mg 0.01N hydrochloric acid q.s. double-distilledwater ad 10.0 mL

The preparation of any the above mentioned formulations can be donefollowing standard procedures.

Biological Assay

The in-vitro effect of the compounds of the invention can be shown withthe following biological assays.

PDE9A2 Assay Protocol:

The PDE9A2 enzymatic activity assay was run as scintillation proximityassay (SPA), in general according to the protocol of the manufacturer(GE Healthcare, former Amersham Biosciences, product number: TRKQ 7100).As enzyme source, lysate (PBS with 1% Triton X-100 supplemented withprotease inhibitors, cell debris removed by centrifugation at 13.000 rpmfor 30 min) of SF 9 cell expressing the human PDE9A2 was used. The totalprotein amount included in the assay varied upon infection andproduction efficacy of the SF9 cells and lay in the range of 0.1-100 ng.

In general, the assay conditions were as follows:

-   -   total assay volume: 40 microlitre    -   protein amount: 0.1-50 ng    -   substrate concentration (cGMP): 20 nanomolar; ˜1 mCi/l    -   incubation time: 60 min at room temperature    -   final DMSO concentration: 0.2-1%

The assays were run in 384-well format. The test reagents as well as theenzyme and the substrate were diluted in assay buffer. The assay buffercontained 50 mM Tris, 8.3 mM MgCl₂, 1.7 mM EGTA, 0.1% BSA, 0.05% Tween20; the pH of assay buffer was adjusted to 7.5. The reaction was stoppedby applying a PDE9 specific inhibitor (e.g. compounds according to WO2004/099210 or WO 2004/099211, like one of the enantiomers of example37, e.g.1-(2-Chlorophenyl)-6-[2R)-3,3,3-trifluoro-2-methyl-propyl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one)in excess.

References:

Wunder F, Tersteegen A, Rebmann A, Erb C, Fahrig T, Hendrix M.Characterization of the first potent and selective PDE9 inhibitor usinga cGMP reporter cell line. Molecular Pharmacology. 2005 December;68(6):1775-81.

van der Staay F J, Rutten K, Barfacker L, Devry J, Erb C, Heckroth H,Karthaus D, Tersteegen A, van Kampen M, Blokland A, Prickaerts J,Reymann K G, Schröder U H, Hendrix M. The novel selective PDE9 inhibitorBAY 73-6691 improves learning and memory in rodents. Neuropharmacology.2008 October; 55(5):908-18.

PDE1C Assay Protocol:

The assay was run in an analogous manner to the PDE9A2 assay, with thefollowing differences: instead of PDE9A2, PDE1C was used and the assaybuffer contained in addition 50 nM Calmodulin, 3 mM CaCl₂. The reactioncan be stopped by applying the same inhibitor than the one that isoutlined above(1-(2-Chlorophenyl)-6-[2R)-3,3,3-trifluoro-2-methyl-propyl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one).

Determination of IC₅₀:

IC₅₀ can be calculated with GraphPadPrism or other suited softwaresetting the positive control as 100 and the negative control as 0. Forcalculation of IC₅₀ dilutions of the test compounds (substrates) are tobe selected and tested following the aforementioned protocol.

Data

In the following IC₅₀ values for PDE9A2 inhibition [nanomolar (nM)]illustrate that the compounds according to the present invention inhibitPDE9, specifically PDE9A2. This evidences that the compounds provideuseful pharmacological properties. The examples are not meant to belimiting.

The table also provides selectivity values (Selectivity) that show apreference of the compounds for PDE9A versus PDE1C. Selectivity is theratio (IC₅₀ for PDE1C inhibition [nanomolar (nM)])/(IC₅₀ for PDE9A2inhibition [nanomolar (nM)]).

The example numbers refer to the final examples as outlined in thesection Exemplary embodiments and as defined by the above compoundfamily table (embodiment 25).

All data can be measured according to the procedure described herein.The definition enantiomer 1 or enantiomer 2 is related to the elutionorders of enantiomers in chiral SFC and chiral HPLC.

IC₅₀ Compound PDE9A2 family Example No. [nanomolar] Selectivity A  1*450 3 B  2* 5 143 C  3* 23 34 D  4* 242 22 E  5* 60 14 F  6* 58 15 G1 7* 31 15 G2  8* 85 63 H1  9* 19 46 H2 10* 13 120 I 11* 233 ≧43 J 12* 8038 K 13* 7 328 K 14 (enantiomer 1) 473 4.3 K 15 (enantiomer 2) 4 424 L16* 5 245 M 17* 16 78 M 18 (enantiomer 1) 5 255 M 19 (enantiomer 2) 13450.61 N 20* 31 68 O 21* 433 10 P 22* 21 49 Q 23 23 187 Q 24(enantiomer 1) 218 8.9 Q 25 (enantiomer 2) 7 197 R 29* 11 117 R 30(enantiomer 1) 304 4.95 R 31 (enantiomer 2) 7 186 S 32* 7 117 S 33(enantiomer 1) 4 181 S 34 (enantiomer 2) 388 1.68 T 26* 32 >400 T 27(enantiomer 1) 11 250 T 28 (enantiomer 2) 360 7 *trans racemic mixture

In-Vivo Effect:

It is believed that the positive in-vitro efficacy results of thecompounds of the present invention translate in positive in-vivoefficacy.

The in-vivo effect of the compounds of this invention can be tested inthe Novel Object Recognition test according to the procedure ofPrickaerts et al. (Neuroscience 2002, 113, 351-361), the socialrecognition test or the T-maze spontaneous alternation test according tothe procedures described by van der Staay et al. (Neuropharmacology2008, 55, 908-918). For further information concerning biologicaltesting one is also referred to these two citations.

Besides the inhibition property toward the target PDE9, compoundsaccording to the present invention may provide further advantageouspharmacokinetic properties.

E.g. compounds according to the invention may show one or moreadvantages in the area of safety, balanced metabolism, low risk ofcausing drug-drug interaction and/or balanced clearance.

Compounds also might show one or more additional or alternativeadvantages in the area of bioavailability, high fraction absorbed, bloodbrain transport properties, a favourable (e.g. high mean) residence time(mrt), favourable exposure in the effect compartment and so on.

Chemical Manufacture

Abbreviations:

-   -   Burgess-reagent        (methoxycarbonylsulfamoyl)-triethylammonium-N-betain    -   Lawesson's reagent        2,4-bis-(4-methoxy-phenyl)-[1,3,2,4]dithiadiphosphetane        2,4-disulfide    -   APCI Atmospheric pressure chemical ionization    -   ACN acetonitrile    -   CDI 1,1′-carbonyldiimidazole    -   DEA diethylamine    -   DIPEA diisopropylethylamine    -   DME 1,2-dimethoxyethane    -   DMF dimethylformamide    -   ESI electrospray ionization (in MS)    -   EtOH ethanol    -   Exp. example    -   h hour(s)    -   HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium        hexafluorophosphate    -   HPLC high performance liquid chromatography    -   HPLC-MS coupled high performance liquid chromatography-mass        spectrometry    -   M molar (mol/L)    -   MeOH methanol    -   min minutes    -   MS mass spectrometry    -   NMP 1-methyl-2-pyrrolidinone    -   R_(t) retention time (in HPLC)    -   SFC supercrticial fluid chromatography    -   TBTU O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium        tetrafluoroborate    -   TFA trifluoroacetic acid    -   THF tetrahydrofuran    -   TLC thin-layer chromatography

LC-MS Methods:

Method 1

MS apparatus type: Waters Micromass ZQ; HPLC apparatus type: WatersAlliance 2695, Waters 2996 diode array detector; column: VarianMicrosorb 100 C18, 30×4.6 mm, 3.0 μm; eluent A: water+0.13% TFA, eluentB: ACN; gradient: 0.0 min 5% B→0.18 min 5% B→2.0 min 98% B→2.2 min 98%B→2.3 min 5% B→2.5 min 5% B; flow rate: 3.5 mL/min; UV detection:210-380 nm

Method 2

MS apparatus type: Waters Micromass ZQ; HPLC apparatus type: WatersAlliance 2695, Waters 2996 diode array detector; column: VarianMicrosorb 100 C18, 30×4.6 mm, 3.0 μm; eluent A: water+0.13% TFA, eluentB: MeOH; gradient: 0.0 min 5% B→0.35 min 5% B→3.95 min 100% B→4.45 min100% B→4.55 min 5% B→4.9 min 5% B; flow rate: 2.4 mL/min; UV detection:210-380 nm.

Method 3

MS apparatus type: Waters Micromass ZQ; HPLC apparatus type: WatersAlliance 2695, Waters 2996 diode array detector; column: VarianMicrosorb C18, 20×4.6 mm, 5.0 μm; eluent A: water+0.15% TFA, eluent B:MeOH; gradient: 0.0 min 5% B→0.25 min 5% B→1.90 min 100% B→2,05 min 100%B→2.15 min 5% B→2.25 min 5% B; flow rate: 5.2 mL/min; UV detection:210-400 nm.

Method 1E Hydro

Instrument: LC/MS ThermoFinnigan. Hplc Surveyor DAD, MSQ Quadrupole;column: Synergi Hydro-RP80A, 4 um, 4.60×100 mm; eluent A: 90% water+10%acetonitrile+ammonium formate 10 mM; eluent B=ACN 90%+10% H₂O+NH₄COOH 10mM; gradient: A (100) for 1.5 min, then to B (100) in 10 min for 1.5min; flow rate: 1.2 mL/min; UV Detection: 254 nm; Ion source: APCI.

Chiral SFC Methods:

Method 4

SFC apparatus type: Berger “Analytix”; column: Daicel IC, 250 mm×4.6 mm,5.0 μm; eluent: CO₂/25% MeOH/0.2% DEA (isocratic); flow rate: 4.0mL/min, 10 min; temperature: 40° C.; UV detection: 210/220/254 nm.

Method 5

SFC apparatus type: Berger “Analytix”; column: Daicel ADH, 250 mm×4.6mm, 5.0 μm; eluent: CO₂/25% MeOH/0.2% DEA (isocratic); flow rate: 4.0mL/min, 10 min; temperature: 40° C.; UV detection: 210/220/254 nm.

Chiral HPLC Methods:

Method 6:

HPLC apparatus type: Agilent 1100; column: Daicel chiralcel OJ-H, 250mm×4.6 mm, 5.0 μm; eluent: hexane/EtOH80:20; flow rate: 1 mL/min,Temperature: 25° C.; UV Detection: variable (200-500 nm).

Method 6.1:

HPLC apparatus type: Agilent 1100; column: Daicel chiralcel OJ-H, 250mm×4.6 mm, 5.0 μm; eluent: hexane/EtOH 85:15; flow rate: 1 mL/min,Temperature: 25° C.; UV Detection: variable (200-500 nm).

Method 7:

HPLC apparatus type: Agilent 1100; column: Chiralpak AD-H, 250 mm×4.6mm, 5.0 μm; eluent: hexane/isopropanol 80:20; flow rate: 1 mL/min,Temperature: 25° C.; UV Detection: variable (200-500 nm).

HPLC apparatus type: Agilent 1100; column: Chiralpak AD-H, 250 mm×4.6mm, 5.0 μm; eluent: hexane/isopropanol 80:20; flow rate: 1 mL/min,Temperature: 25° C.; UV Detection: variable (200-500 nm).

Microwave Heating:

-   -   Discover® CEM instruments, equipped with 10 and 35 mL vessels;    -   Biotage Initiator Sixty.

General Comment Concerning the Presentation of the Structures

Compounds with stereogenic centre(s): The structures depicted in theexperimental section below will not necessarily show all thestereochemical possibilities of the compounds but only one. However, insuch cases a term like “trans-racemic mixture” or “cis-racemic mixture”is added next to the depicted structure in order to indicate the otherstereochemical options.

An example is given below. The presented structural formula is

The added term “trans-racemic mixture” points to the secondstereochemical option:

Thus, the manufactured compound is a mixture of

This principle applies to other depicted structures as well.

Starting Compounds:

Example 1A Trans-Racemic Mixture

2.00 g (13.9 mmol) trans-cyclobutan-1,2-dicarboxylic acid were mixedwith 16 mL EtOH at 0° C. and 2.21 mL (30.5 mmol) thionylchloride wereslowly added. The mixture was allowed to warm to room temperature andstirred for 1 h. The solvent was removed under reduced pressure and theproduct was filtered through a pad of activated basic alumina. 2.71 g(98%) of the product were obtained.

HPLC-MS (Method 1): R_(t)=1.34 min

MS (ESI pos): m/z=201 (M+H)⁺

The following example was synthesized in analogy to the preparation ofExample 1A, using the corresponding diacid as starting material.

MS (ESI Exam- R_(t) pos, ple structure starting material [min] m/z) Exp.1B cis- race- mic mix- ture

1.12 (Meth- od 3) 201 (M + H)⁺

Example 2A Racemic Mixture

8.00 g (89.7 mmol) 2-amino-propionic acid were mixed with 88.0 mL (0.93mol) acetic anhydride and 88.0 mL pyridine. The reaction mixture wasstirred at 100° C. for 135 min. The solvent was removed under reducedpressure. Toluene was added to the residue and the solvent was removedunder reduced pressure, then 204 mL (816 mmol) HCl (4 M aqueoussolution) was added and the mixture was refluxed for 3 h. The solventwas removed under reduced pressure. 1-Butanol (20 mL) was added to theresidue and the solvent was removed under reduced pressure. 11.6 g ofthe title compound were obtained as hydrochloride salt.

MS (ESI pos): m/z=88 (M+H)⁺

Example 3A Trans-Racemic Mixture

1.00 g (4.09 mmol)5-Amino-1-(4,4-difluoro-cyclohexyl)-1H-pyrazole-4-carboxylic acid amide(see PCT patent application WO 2010/026214, example 8A) was mixed with15 mL of anhydrous EtOH, 2.46 g (12.3 mmol) of Example 1A and 0.66 g(16.4 mmol) of sodium hydride (60% suspension in mineral oil) wereadded. The reaction mixture was heated to 140° C. for 30 min in amicrowave oven. The mixture was cooled to room temperature and sodiumhydroxide solution (4 M aqueous solution) was added. The solvent wasremoved under reduced pressure. The residue was purified by preparativeHPLC (eluent A: water+0.13% TFA, eluent B: MeOH). 0.70 g (49%) of theproduct were obtained.

HPLC-MS (Method 1): R_(t)=1.24 min

MS (ESI pos): m/z=353 (M+H)⁺

The following examples were synthesized in analogy to the preparation ofExample 3A, using the corresponding amide and ester as startingmaterials (for starting materials it is referred to PCT patentpublications WO 2010/026214, WO 2009/121919 and WO 2004/09921).

MS starting (ESI starting material: material: R_(t) pos, Examplestructure amide ester [min] m/z) Exp. 3B (trans- racemic mixture)

5-amino-1- (tetrahydro- pyran-4-yl)-1H- pyrazole-4- carboxylic acidamide (see WO 2009/121919, example 11B) Exp. 1B 1.07 (Meth- od 3) 319(M + H)⁺ Exp. 3C (trans- racemic mixture)

5-amino-1-(4- methyl-pyridin- 3-y1)-1H- pyrazole-4- carboxylic acidamide (see WO 2004/099211, example 35A) Exp. 1A 0.81 (Method 1); 326(M + H)⁺

Example 4A Trans-Racemic Mixture

0.200 g (0.568 mmol) Example 3A were mixed with 0.157 mL (1.14 mmol)triethylamine and 5 mL DMF. To the mixture were added 0.237 g (0.624mmol) HATU, then the reaction mixture was stirred at room temperaturefor 10 min. To the mixture were added 0.042 g (0.568 mmol) acetic acidhydrazide and the reaction mixture was stirred at room temperature for 1h. The mixture was purified by preparative HPLC (eluent A: water+0.13%TFA, eluent B: MeOH). 30 mg of the product were obtained.

HPLC-MS (Method 1): R_(t)=1.03 min

MS (ESI pos): m/z=409 (M+H)⁺

Example 5A trans-Racemic Mixture

0.150 g (0.426 mmol) of Example 3A were mixed with 2 mL THF. The mixturewas cooled to 0° C. and 0.036 mL (0.426 mmol) oxalylchloride and onedrop of DMF were added. The reaction mixture was stirred at 0° C. for 1h. To the reaction mixture were added 2 mL ACN and 0.426 mL (0.851 mmol)trimethylsilyldiazomethane (2 M in hexane). The mixture was stirred for2 h, then 0.213 mL HCl (4 M in dioxane) was slowly added. The reactionwas stirred for 3 h. To the mixture were added ethylacetate andsaturated aqueous sodium hydrogen carbonate solution. The organic layerwas washed with water and brine and dried over sodium sulfate. Thesolvents were partially evaporated until volume of approximately 2 mLwas reached. The mixture was taken to the next step without furtherpurification.

HPLC-MS (Method 1): R_(t)=1.40 min

MS (ESI pos): m/z=385/387 (C1)

The following example was synthesized in analogy to the preparation ofExample 5A, using the corresponding acid as starting material.

MS (ESI Exam- starting R_(t) pos, ple structure material [min] m/z) Exp.5B trans- race- mic mix- ture

Exp. 3B 1.12 (Meth- od 1) 351/ 353 (Cl)

Example 6A Trans-Mixture of Stereoisomers

0.200 g (0.628 mmol) of Example 3B were mixed with 1 mL DMF. 0.261 mL(1.89 mmol) triethylamine and 0.222 g (0.691 mmol) of TBTU were added.The reaction mixture was stirred at room temperature for 10 min. Then0.078 g (0.628 mmol) of Example 2A was added and the mixture was stirredat room temperature for 1 h. The mixture was purified by preparativeHPLC (eluent A: water+0.13% TFA, eluent B: MeOH). 190 mg of the productwere obtained.

HPLC-MS (Method 3): R_(t)=1.03 min

MS (ESI pos): m/z=388 (M+H)⁺

Example 7A Trans-Racemic Mixture

0.200 g (0.628 mmol) of Example 3B were mixed with 1 mL DMF. 0.174 mL(1.26 mmol) triethylamine and 0.222 g (0.691 mmol) of TBTU were added.The reaction mixture was stirred at room temperature for 10 min. Then0.066 g (0.628 mmol) 2,2-dimethoxy-ethylamine was added and the mixturewas stirred at room temperature for 1 h. Then HCl (2 M aqueous solution)was added and the mixture was purified by preparative HPLC (eluent A:water+0.13% TFA, eluent B: MeOH). The residue was mixed with 5 mLacetone and 1 mL HCl (2 M aqueous solution) and stirred overnight undernitrogen. Then the mixture was extracted with DCM. The organic layer wasevaporated and purified by preparative HPLC (eluent A: water+0.13% TFA,eluent B: MeOH). 170 mg of the product was obtained.

HPLC-MS (Method 3): R_(t)=1.01 min

MS (ESI pos): m/z=360 (M+H)⁺

Example 8A Trans-Mixture of Stereoisomers

0.200 g (0.568 mmol) of Example 3A was mixed with 1.0 mL DMF. 0.432 mL(2.84 mmol) DIPEA and 0.200 g (0.624 mmol) TBTU were added. The reactionmixture was stirred at room temperature for 10 min. Then 0.140 g (1.14mmol) of Example 2A were added and the mixture was stirred at roomtemperature for 2 h. The mixture was purified by preparative HPLC(eluent A: water+0.13% TFA, eluent B: MeOH). 70 mg (29%) of the productwas obtained.

HPLC-MS (Method 1): R_(t)=1.23 min

MS (ESI pos): m/z=422 (M+H)⁺

The following examples were synthesized in analogy to the preparation ofExample 8A, using the corresponding nucleophiles as starting materials.

MS (ESI starting pos, Example structure material R_(t) [min] m/z) Exp.8B trans-racemic mixture

  hydrochloride 1.31 (method 1) 396 (M + H)⁺ Exp. 8C trans-mixture ofstereoisomers

410 (M + H)⁺ Exp. 8D trans-mixture of stereoisomers

1.12 (method 1) 410 (M + H)⁺ Exp. 8E trans-racemic mixture

hydrazine hydrate 0.99 (method 1) 367 (M + H)⁺

Example 9A Trans-Racemic Mixture

0.182 g (0.430 mmol) Dess-Martin periodinane were mixed with 2.5 mL DCM.0.160 g (0.391 mmol) Example 8D in 2.5 mL DCM was added at roomtemperature. The reaction mixture stirred at room temperature for 30 minand at 30° C. for 30 min. To the mixture were added 10 mL sodiumthiosulfate solution (10% in water) and 10 mL saturated sodium hydrogencarbonate solution and the mixture was stirred for 20 min. The organiclayer was separated and the aqueous layer was extracted with DCM. Theorganic layer was washed with saturated sodium hydrogen carbonatesolution, dried and evaporated. 93 mg (58%) of the product wereobtained.

HPLC-MS (Method 1): R_(t)=1.18 min

MS (ESI pos): m/z=408 (M+H)⁺

The following example was synthesized in analogy to the preparation ofExample 9A, using the corresponding alcohol as starting material.

Exam- starting ple structure material Exp. 9B trans- mix- ture ofstereo- isomers

Exp. 8C

Example 10A Trans-Mixture of Stereoisomers

0.450 g of Example 3C was mixed with 3.5 mL DMF and 0.273 g (2.21 mmol)Example 2A. 1.00 mL (6.64 mmol) DIPEA and 0.390 g (1.22 mmol) TBTU wereadded and the mixture was stirred for 1 h. The mixture was purified bypreparative HPLC (eluent A: water+0.13% TFA, eluent B: MeOH). 360 mg(83%) of the product was obtained.

HPLC-MS (Method 1): R_(t)=0.85 min

MS (ESI pos): m/z=395 (M+H)⁺

Example 11A Trans-Racemic Mixture

300 mg (1.23 mmol) of5-amino-1-(4,4-difluoro-cyclohexyl)-1H-pyrazole-4-carboxylic acid amide(see WO 2010/026214, example 8A) were mixed with 4 mL anhydrous EtOH,326 mg (3.07 mmol) trans-cyclobutane-1,2-dicarbonitrile and 0.197 g(4.91 mmol) of sodium hydride (60% suspension in mineral oil) undernitrogen. The reaction mixture was heated to 140° C. for 45 min in amicrowave oven. The solvent was removed under reduced pressure. Theresidue was purified by preparative HPLC (eluent A: water+0.13% TFA,eluent B: MeOH). 210 mg (51%) of the title compound were obtained.

HPLC-MS (Method 3): R_(t)=1.19 min

MS (ESI pos): m/z=334 (M+H)⁺

Example 11B Trans-Racemic Mixture

To a solution of 0.8 g (3.805 mmol) of5-amino-1-(tetrahydro-pyran-4-yl-1-H-pyrazole-4-carboxylic acid amide(see PCT patent application WO2010/026214) in 8 mL anhydrous EtOH, 0.457g (19.6 mmol) of sodium hydride (60% suspension in mineral oil) wereadded at room temperature under nitrogen. After 1 h under stirring, 1.2g (11.42 mmol) of trans-cyclobutane-1,2-dicarbonitrile were added andthe reaction mixture was heated to 140° C. for 45 min in a microwaveoven. The solvent was removed under reduced pressure. The residue wasdissolved in DCM, water was added and phases were separated. Organiclayers were dried over sodium sulphate and evaporated under reducedpressure. The crude was purified by flash cromatography (Cy/EtOAc from80/20 to 100%) to obtain the title compound as yellow solid. (0.64 g,55%)

HPLC-MS (Method 1Eh): R_(t)=6.21 min

MS (APCI): m/z=300 (M+H)⁺

Example 11C Trans-Racemic Mixture

To a solution of 0.85 g (3.91 mmol) of5-amino-1-(4-methyl-pyridin-3-yl)-1H-pyrazole-4-carboxylic acid amide(see PCT patent application WO 2004/09921) in 10 mL anhydrous EtOH, 0.47g (11.74 mmol) of sodium hydride (60% suspension in mineral oil) wereadded at room temperature under nitrogen. After 1 h under stirring, 1.28g (11.74 mmol) of trans-cyclobutane-1,2-dicarbonitrile were added andthe reaction mixture was heated to 140° C. for 45 min in a microwaveoven. The reaction mixture was then loaded on SCX cartridge, ammoniafractions were collected and evaporated and the residue was purified byflash cromatography (DCM/MeOH 90:10) to obtain the title compound aswhite solid. (0.63 g, 52%).

HPLC-MS (Method 1Eh): R_(t)=5.92 min

MS (APCI pos): m/z=307 (M+H)⁺

Example 12A Trans-Racemic Mixture

190 mg (0.570 mmol) of Example 11A were mixed with 0.281 mL toluene and0.093 mL (2.30 mmol) anhydrous MeOH. 0.103 mL (1.45 mmol) acetylchloridewere added slowly at 0° C. The mixture was stirred at room temperaturefor 12 h. The solvent was removed under reduced pressure. To the residue0.5 mL MeOH were added. Then 0.407 mL (2.85 mmol) ammonia (7 M in MeOH)were added at 0° C. and the mixture was allowed to warm to roomtemperature. After 30 min the reaction mixture was treated with waterand the pH was adjusted to pH=1 by addition of TFA. The mixture waspurified by preparative HPLC (eluent A: water+0.13% TFA, eluent B: MeOH)yielding 110 mg (42%) of the product were as trifluoroacetic acid salt.

HPLC-MS (Method 3): R_(t)=1.04 min

MS (ESI pos): m/z=351 (M+H)⁺

Example 12B Trans-Racemic Mixture

To a mixture of dry EtOH (5 mL) and dry CHCl₃ (5 mL) cooled at 0° C.,acetylchloride (2.27 mL, 30.82 mmol) was added slowly and mixture leftunder stirring for 20 min 0° C. A solution of Example 11B (0.410 g,1.027 mmol) in dry CHCl₃ (5 mL) was added dropwise and the mixturestirred at room temperature overnight. Solvents were evaporated underreduced pressure, residue dissolved in dry EtOH (5 mL) and 6.4 mL of a7.0M solution of ammonia in MeOH (30.82 mmol) were added. The mixturewas stirred at room temperature for 12 h. The solvent was removed underreduced pressure. The final product was obtained as hydrochloride andused for the next step without further purification. (0.37 g, content50% estimated by HPLC-MS).

HPLC-MS (Method 1Eh): R_(t)=5.38 min

MS (APCI pos): m/z=317 (M+H)⁺

Example 12C Trans-Racemic Mixture

To a mixture of dry EtOH (4 mL) and dry CHCl₃ (10 mL) cooled at 0° C.,acetylchloride (4.38 mL, 61.7 mmol) was added slowly and mixture leftunder stirring for 20 min 0° C. A solution of Example 11C (0.63 g, 2.057mmol) in dry CHCl₃ (5 mL) was added dropwise and the mixture stirred atroom temperature overnight. Solvents were evaporated under reducedpressure, residue dissolved in dry MeOH (10 mL) and 10.3 mL of a 7.0Msolution of ammonia in MeOH (72 mmol) were added. The mixture wasstirred at room temperature for 12 h. The solvent was removed underreduced pressure. The final product, obtained as hydrochloride salt, wasused as such in the next step without further purification. (0.85 g,content 84%, estimated by 1H-NMR).

HPLC-MS (Method 1Eh): R_(t)=5.15 min

MS (APCI pos): m/z=324 (M+H)⁺

Example 13A Trans-Racemic Mixture

To a solution of 1.6 g (10.24 mmol) of 2-acetyl-cyclobutanecarboxylicacid methyl ester (prepared as described in J. Med. Chem, 25, 109, 1982)in dry EtOH (12 mL), propargylamine (1.4 mL, 20.4 mmol) was addedfollowed by 0.122 g (0.307 mmol) of sodium gold trichloride. Thereaction mixture was heated to 140° C. for 45 min in a microwave oven,solid was filtered and the organic evaporated. Crude was purified byflash cromatography (Cy/EtOAc 70:30) to obtain the title compound asyellow green oil. (0.18 g, 9.2%).

HPLC-MS (Method 1Eh): R_(t)=0.87 min

MS (APCI pos): m/z=192 (M+H)⁺

Exemplary Embodiments

Example 1 Trans-Racemic Mixture

22.0 mg (0.306 mmol) of propan-2-one oxime were mixed with 2 mLanhydrous THF and 0.471 mL (1.22 mmol) n-butyllithium (2.6 mol/L intoluene) was added carefully to the mixture. The reaction mixture wasstirred at room temperature for 30 min 0.110 g (0.278 mmol) of Example8B in 1 mL anhydrous THF were carefully added during 10 min. After 30min the reaction mixture was added to a mixture of 0.28 mL H₂SO₄ and 4mL THF/water (4:1). The mixture was refluxed for 1.5 h. Saturatedaqueous sodium hydrogen carbonate solution was added and extracted withethylacetate. The organic layer was dried and the solvents wereevaporated. The residue was purified by preparative HPLC (eluent A:water+0.13% TFA, eluent B: MeOH). 8 mg (8%) of the product wereobtained.

HPLC-MS (Method 1): R_(t)=1.40 min

MS (ESI pos): m/z=390 (M+H)⁺

Example 2 Trans-Racemic Mixture

0.190 g of Example 6A were mixed with 3 mL DME and 0.273 g (1.14 mmol)Burgess reagent. The reaction mixture was heated to 130° C. for 1 h in amicrowave oven. The solvent was evaporated and the residue purified bypreparative HPLC (eluent A: water+0.13% TFA, eluent B: MeOH). 70 mg(55%) of the product were obtained.

HPLC-MS (Method 1): R_(t)=1.11 min

MS (ESI pos): m/z=370 (M+H)⁺

The following examples were synthesized in analogy to the preparation ofExample 2, using the corresponding amides as starting materials.

MS (ESI starting pos, Example structure material R_(t) [min] m/z) Exp. 3trans- racemic mixture

Exp. 7A 1.17 (Method 3) 342 (M + H)⁺ Exp. 4 trans- racemic mixture

Exp. 4A 1.20 (Method 1) 391 (M + H)⁺ Exp. 5 trans- racemic mixture

Exp. 8A 1.38 (method 1) 404 (M + H)⁺ Exp. 6 trans- racemic mixture

Exp. 9A 1.37 (method 1) 390 (M + H)⁺ Exp. 7 trans- racemic mixture

Exp. 9B 1.42 (method 3) 390 (M + H)⁺ Exp. 8 trans- racemic mixture

Exp. 10A 0.97 (method 1) 377 (M + H)⁺

Example 9 Trans-Racemic Mixture

To a solution of Example 5A, synthesized starting from 0.426 mmol ofExample 3A as described above, was added dropwise 0.062 g (0.832 mmol)thioacetamide in 2 mL EtOH. The reaction mixture was stirred overnight.The mixture was purified by preparative HPLC (eluent A: water+0.13% TFA,eluent B: MeOH). 62 mg of the title compound were obtained.

HPLC-MS (Method 1): R_(t)=1.37 min

MS (ESI pos): m/z=406 (M+H)⁺

The following examples were synthesized in analogy to the preparation ofExample 9, using the corresponding starting materials.

MS starting (ESI starting material: material: pos, Example structurenucleophile chloroketon R_(t) [min] m/z) Exp. 10 trans- racemic mixture

thioacetamide Exp. 5B 1.21 (Method 3) 372 (M + H)⁺ Exp. 11 trans-racemic mixture

1,1-dimethyl- thiourea Exp. 5A 1.15 (Method 3) 435 (M + H)⁺ Exp. 12trans- racemic mixture

thiourea Exp. 5A 1.15 (Method 3) 407 (M + H)⁺

Example 13 Trans-Racemic Mixture

100 mg (0.215 mmol) of Example 12A were mixed with 1.00 mL (6.07 mmol)1,1,3,3-tetramethoxypropane. The reaction mixture was heated to 175° C.for 1 h using a microwave oven. The reaction mixture was treated withDCM/MeOH and one drop of triethylamine. The solvents were removed underreduced pressure. The mixture was purified by preparative HPLC (eluentA: water+0.13% TFA, eluent B: MeOH) yielding 45 mg (54%) of the titlecompound.

HPLC-MS (Method 3): R_(t)=1.36 min

MS (ESI pos): m/z=387 (M+H)⁺

The enantiomers of the title compound were separated by HPLC using achiral stationary phase.

Method for Enantioseparation:

HPLC apparatus type: Berger Minigram; column: Daicel IC, 5.0 μm, 250mm×10 mm; method: eluent CO₂/30% MeOH/0.2% DEA (isocratic); flow rate:10 mL/min,

Temperature: 40° C.; pressure: 100 bar; UV Detection: 210 nm

Example structure R_(t) [min] Exp. 14 trans- enantiomer 1

3.15 (Method 4) Exp. 15 trans- enantiomer 2

3.78 (Method 4)

The following example was synthesized in analogy to the preparation ofExample 13, using the corresponding dialdehydediacetal as startingmaterial.

MS (ESI Exam- starting R_(t) pos, ple structure material [min] m/z) Exp.16 trans- racemic mixture

1,1,3,3- tetra- ethoxy- 2- methyl- propane 1.42 (Meth- od 3) 401 (M +H)⁺

Example 17 Trans-Racemic Mixture

176 mg (0.431 mmol) of Example 4A were mixed with 3 mL THF and 122 mg(0.302 mmol) Lawesson's reagent at room temperature. Then the mixturewas stirred for 6 h at 60° C. The reaction mixture was treated withwater and diluted with DCM. The mixture was filtered over basic aluminaand eluted with DCM and EtOH. The solvents were removed under reducedpressure. The residue was purified by preparative HPLC (eluent A:water+0.13% TFA, eluent B: MeOH). 45 mg (26%) of the product wereobtained.

HPLC-MS (Method 3): R_(t)=1.37 min

MS (ESI pos): m/z=407 (M+H)⁺

The enantiomers of the title compound were separated by HPLC using achiral stationary phase.

Method for Enantioseparation:

HPLC apparatus type: Berger Minigram; column: Daicel ADH, 5.0 μm, 250mm×10 mm; method: eluent CO₂/30% MeOH/0.2% DEA (isocratic); flow rate:10 mL/min,

Temperature: 40° C.; pressure: 100 bar; UV Detection: 210 nm

Example structure R_(t) [min] Exp. 18 trans- enanti- omer 1 (S,S)

2.47 (Method 5) Exp. 19 trans- enanti- omer 2 (R,R)

2.96 (Method 5)

Single crystals of example 19 have been prepared by recrystallisationfrom ethylacetate and subjected to X-ray crystal analysis. The dataallowed to determine the absolute configuration of example 19 to be(R,R).

Experimental: Data collection and reduction: Data collected on Saturn944 CCD mounted on AFC11K goniometer, Radiation: Cu Kα from RU200rotating anode and RIGAKU VARIMAX optics, Temperature: 100K.

Summary of Data Collection Statistics

Spacegroup P2₁ Unit cell dimensions 8.560(2) 6.844(1) 15.603(3) 90.0098.82(3) 90.00 Resolution range 15.42-0.85 (0.88-0.85)  Total number ofreflections 10857 Number of unique reflections  1588 Average redundancy6.84 (2.46) % completeness 95.7 (79.1) Rmerge 0.064 (0.118) Output<I/sigI> 27.7 (7.9)  Values in ( ) are for the last resolution shell.

Refinement Statistics:

Final Structure Factor Calculation for example 19 in P2₁

Total number of l.s. parameters=255

GooF=S=1.154

Weight=1/[sigma^2(Fo^2)+(0.0421*P)^2+0.38*P] where P=(Max(Fo^2,0)+2*Fc{circumflex over (2)})/3

R1=0.0695 for 2207 Fo>4sig(Fo) and 0.0829 for all 2334 data, wR2=0.1646,

Flack×parameter=0.09(3).

Example 20 Trans-Racemic Mixture

0.060 g of Example 10A were mixed with 4 mL anhydrous dioxane and 0.074g (0.180 mmol) Lawesson's reagent. The reaction mixture was heated to120° C. for 1 h in a microwave oven. The mixture was filtered over basicalumina and eluted with DCM and MeOH. The solvents were removed underreduced pressure. The residue was purified by preparative HPLC (eluentA: water+0.13% TFA, eluent B: MeOH). 22 mg of the product were obtainedas salt with TFA.

HPLC-MS: (Method 1): R_(t)=0.94 min

MS (ESI pos): m/z=393 (M+H)⁺

Example 21 Trans-Racemic Mixture

0.190 g (0.519 mmol) Example 8E were mixed with 1.38 mL (8.31 mmol)triethoxymethane. The mixture was stirred for 1.5 h at 150° C. Thereaction mixture was allowed to cool to room temperature and purified bypreparative HPLC (eluent A: water+0.13% TFA, eluent B: MeOH). 90 mg(46%) of the product were obtained.

HPLC-MS (Method 1): R_(t)=1.19 min

MS (ESI pos): m/z=377 (M+H)⁺

Example 22 Trans-Racemic Mixture

13 mg (0.10 mmol) CuCl₂, 26 mL (0.22 mmol) tert-butyl-nitrite were mixedwith ACN. A mixture of 22 mg (0.05 mmol) Example 12 in ACN was carefullyadded at 0° C. The mixture was stirred for 1 h at 25° C. Additional 9 mg(0.07 mmol) CuCl₂ and 13 mL (0.11 mmol) tert-butyl-nitrite was added andstirred another 20 min. The solvents were removed under reducedpressure. The residue was taken up in DCM and extracted with HCl andwater. The mixture was purified by preparative HPLC (eluent A:water+0.13% TFA, eluent B: MeOH) yielding2.1 mg (9%) of the product. .

HPLC-MS: (Method 3): R_(t)=1.46 min

MS (ESI pos): m/z=426/428 (Cl) (M+H)⁺

Example 23 Trans-Racemic Mixture

180 mg (0.26 mmol, content 50%, estimated by HPLC-MS) of Example 12bwere mixed with 1.00 mL (6.07 mmol) 1,1,3,3-tetramethoxypropane. Thereaction mixture was heated to 175° C. for 1 h using a microwave oven.The reaction mixture was treated with DCM, washed with water. Organiclayers were dried over sodiumsulphate and evaporated under reducedpressure. The crude was purified by flash cromatography (Cy/EtOAc from80/20 to AcOEt/MeOH 96/4) and then with a second flash cromatography(DCM 100% to DCM/EtOH 96/4) to obtain the title compound as beige solid.(0.034 g).

HPLC-MS (Method 1Eh): R_(t)=6.57 min

MS (APCI pos): m/z=353 (M+H)⁺

The enantiomers of the title compound were separated by HPLC using achiral stationary phase.

Method for Enantioseparation:

Semipreparative Conditions:

HPLC semipreparative system: Waters 600 pump; column: Daicel chiralcelOJ-H, 250 mm×20 mm, 5.0 μm; eluent: hexane/EtOH80:20; flow rate: 15mL/min, Temperature: 25° C.; UV Detection: 254 nm

Example structure R_(t) [min] Exp. 24 trans- enantiomer 1

15.604 (Method 6) Exp. 25 trans- enantiomer 2

20.119 (Method 6)

Analytical Conditions

HPLC apparatus type: Agilent 1100; Method 6; column: Daicel chiralcelOJ-H, 250 mm×4.6 mm, 5.0 μm; eluent: hexane/EtOH80:20; flow rate: 1mL/min, Temperature: 25° C.; UV Detection: 254 nm

Example 26 Trans-Racemic Mixture

140 mg (content 84%, 0.33 mmol) of Example 12C were mixed with 1.4 mL of1,1,3,3-tetramethoxypropane and 1.4 mL of NMP. The reaction mixture washeated to 175° C. for 1 h using a microwave oven. The reaction mixturewas then diluted with MeOH and loaded on SCX cartridge Ammonia fractionswere collected and the residue was purified by flash cromatography(Cy/EtOAc from 90/10 to 100%) to obtain the title compound as whitesolid (30 mg).

HPLC-MS (Method 1Eh): R_(t)=6.72 min

MS (APCI pos): m/z=370 (M+H)⁺

The enantiomers of the title compound were separated by HPLC using achiral stationary phase.

Method for Enantioseparation:

Semipreprative Conditions:

HPLC semipreparative system: Waters 600 pump; column: Daicel chiralcelOJ-H, 250 mm×20 mm, 5.0 μm; eluent: hexane/EtOH80:20; flow rate: 15mL/min, Temperature: 25° C.; UV Detection: 230 nm

Example structure R_(t) [min] Exp. 27 trans- enantiomer 1

17.748 (Method 6) Exp. 28 trans- enantiomer 2

20.475 (Method 6)

Analytical Conditions

HPLC apparatus type: Agilent 1100; Method 6; column: Daicel chiralcelOJ-H, 250 mm×4.6 mm, 5.0 μm; eluent: hexane/EtOH80:20; flow rate: 1mL/min, Temperature: 25° C.; UV Detection: 254 nm

Example 29 Trans-Racemic Mixture

To a suspension of 0.132 g (0.63 mmol) of5-amino-1-(tetrahydro-pyran-4-yl)-1-H-pyrazole-4-carboxylic acid amide(see PCT patent application WO2010/026214) in dry EtOH (1.5 mL), 0.066 g(1.66 mmol) of sodium hydride (60% suspension in mineral oil) were addedat room temperature under nitrogen. After 10 min, 0.181 mg (0.945 mmol)of Example 13A were added and the reaction mixture was heated to 140° C.for 40 min in a microwave oven (Power 100W). The reaction mixture wasthen diluted with DCM, water was added, organics separated and driedover sodiumsulphate. Organics were evaporated under reduced pressure andthe crude purified by flash cromatography (DCM/IPA 98:2) to obtain thetitle compound as a white solid. (54 mg, 32%).

HPLC-MS (Method 1Eh): R_(t)=8.01 min

MS (APCI pos): m/z=352 (M+H)⁺

The enantiomers of the title compound were separated by HPLC using achiral stationary phase.

Method for Enantioseparation:

Semipreprative Conditions:

HPLC semipreparative system: Waters 600 pump; column: Daicel chiralcelOJ-H, 250 mm×20 mm, 5.0 μm; eluent: hexane/EtOH85:15; flow rate: 15mL/min, Temperature: 25° C.; UV Detection: 254 nm

Example structure R_(t) [min] Exp. 30 trans- enantiomer 1

14.754 (Method 6.1) Exp. 31 trans- enantiomer 2

16.834 (Method 6.1)

Analytical Conditions

HPLC apparatus type: Agilent 1100; Method 6.1; column: Daicel chiralcelOJ-H, 250 mm×4.6 mm, 5.0 μm; eluent: hexane/EtOH85:15; flow rate: 1mL/min, Temperature: 25° C.; UV Detection: 254 nm

Example 32 Trans-Racemic Mixture

To a suspension of 0.135 g (0.553 mmol) of5-amino-1-(4,4-difluoro-cyclohexyl)-1-H-pyrazole-4-carboxylic acid amide(see PCT patent application WO2010/026214) in dry EtOH (1.5 mL), 0.066 g(1.66 mmol) of sodium hydride (60% suspension in mineral oil) were addedat room temperature under nitrogen. After 10 min, 0.161 mg (0.837 mmol)of Example 13A were added and the reaction mixture was heated to 140° C.for 40 min in a microwave oven (Power 100W). The reaction mixture wasthen diluted with DCM, water was added, organics separated and driedover sodium sulphate. Organics were evaporated under reduced pressureand the crude purified by flash cromatography (Cy/EA from 50:50 to10:90) to obtain the title compound as a white solid. (54 mg, 25%).

HPLC-MS (Method 1Eh): R_(t)=9.63 min

MS (APCI pos): m/z=386 (M+H)⁺

The enantiomers of the title compound were separated by HPLC using achiral stationary phase.

Method for Enantioseparation:

Semipreprative Conditions:

HPLC semipreparative system: Waters 600 pump; Column: Daicel chiralpakAD-H, 250 mm ×20 mm, 5.0 μm; eluent: hexane/Isopropanol 80:20; flowrate: 10 mL/min, Temperature: 25° C.; UV Detection: 260 nm

Example structure R_(t) [min] Exp. 33 trans- enantiomer 1

14.80 (Method 7) Exp. 34 trans- enantiomer 2

20.40 (Method 7)

Analytical Conditions

HPLC apparatus type: Agilent 1100; Method 7; column: Daicel chiralcelAD-H, 250 mm×4.6 mm, 5.0 μm; eluent: hexane/Isopropanol 80:20; flowrate: 1 mL/min, Temperature: 25° C.; UV Detection: 260 nm

The invention claimed is:
 1. A method for the treatment of a cognitiveimpairment of learning and/or memory comprising administering to apatient in need thereof a therapeutically effective amount of a compoundof formula (I)

wherein R¹ is a 5 or 6 membered heteroaryl-group whereby 1, 2, 3 or 4 ofthe ring atoms are heteroatoms that are selected independently of eachother from N, O or S, whereby said 5 or 6 membered aromaticheteroaryl-group optionally may be substituted by 1, 2, 3 or 4substituents, whereby said substituents may be selected independently ofone another from the group consisting of fluorine, chlorine, bromine,HO—, NC—, F₃C—, HF₂C—, FH₂C—, methyl, H₂N—and (CH₃)₂N—; R² is selectedfrom the group consisting of fluorine, NC—, F₃C—, HF₂C—, FH₂C—andmethyl; D is selected from the group consisting of cyclopentyl,cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, 2-, 3- and 4-pyridyl,whereby cyclopentyl and cyclohexyl optionally may be substituted by 1 or2 substituents, whereby said substituents may be selected independentlyof one another from the group consisting of fluorine, NC—, F₃C—,HF₂C—and FH₂C—; whereby tetrahydrofuranyl and tetrahydropyranyloptionally may be substituted by 1 or 2 substituents, whereby saidsubstituents may be selected independently of one another from the groupconsisting of fluorine, NC—, F₃C—, HF₂C—and FH₂C—; whereby pyridyloptionally may be substituted by 1, 2, 3 or 4 substituents, whereby saidsubstituents may be selected independently of one another from the groupconsisting of fluorine, chlorine, bromine, NC—, F₃C—, FH₂C—F₃C—CH₂-,C₁₋₆-alkyl- and C₃₋₇-cycloalkyl, m is selected from 1 or 2; n isselected from 0, 1 or 2, whereby if n =2, these two groups R² areselected independently of one another; or a pharmaceutically acceptablesalt thereof; with the proviso that the compound is not

 be it in the form of any possible stereoisomer or a mixture of all orsome thereof.
 2. The method according to claim 1 wherein the cognitiveimpairment is a consequence of a CNS disease.
 3. The method according toclaim 1 where the cognitive impairment is a consequence ofage-associated learning and memory impairments, age-associated memorylosses, vascular dementia, craniocerebral trauma, stroke, dementiaoccurring after strokes (post stroke dementia), post-traumatic dementia,general concentration impairments, concentration impairments in childrenwith learning and memory problems, Alzheimer's disease, Lewy bodydementia, dementia with degeneration of the frontal lobes, Pick'ssyndrome, Parkinson's disease, progressive nuclear palsy, dementia withcorticobasal degeneration, amyotropic lateral sclerosis (ALS),Huntington's disease, multiple sclerosis, thalamic degeneration,Creutzfeld-Jacob dementia, HIV dementia, epilepsy, temporal lobeepilepsy, schizophrenia, schizophrenia (with dementia), Korsakoffspsychosis or cognitive impairment associated with depression or bipolardisorder.
 4. The method according to claim 1 where the cognitiveimpairment is a consequence of Alzheimer's disease.
 5. The methodaccording to claim 1 where the cognitive impairment is a consequence ofschizophrenia.
 6. The method according to claim 1 where the cognitiveimpairment is a consequence of epilepsy.
 7. The method according toclaim 1 where the cognitive impairment is a consequence of sleepdisorders, bipolar disorder, metabolic syndrome, obesity, diabetesmellitus, hyperglycemia, dyslipidemia, impaired glucose tolerance, or adisease of the testes, brain, small intestine, skeletal muscle, heart,lung, thymus or spleen.
 8. The method according to claim 1, wherein thecompound of formula (I) is

or a pharmaceutically acceptable salt thereof.
 9. The method accordingto claim 1, wherein the compound of formula (I) is

or a pharmaceutically acceptable salt thereof.
 10. The method accordingto claim 1, wherein the compound of formula (I) is

or a pharmaceutically acceptable salt thereof.
 11. The method accordingto claim 1, wherein the compound of formula (I) is

or a pharmaceutically acceptable salt thereof.
 12. The method accordingto claim 1, wherein the compound of formula (I) is

or a pharmaceutically acceptable salt thereof.
 13. The method accordingto claim 1, wherein the compound of formula (I) is

or a pharmaceutically acceptable salt thereof.
 14. The method accordingto claim 1, wherein the compound of formula (I) is

or a pharmaceutically acceptable salt thereof.
 15. The method accordingto claim 1, wherein the compound of formula (I) is

or a pharmaceutically acceptable salt thereof.
 16. The method accordingto claim 1, wherein the compound of formula (I) is

or a pharmaceutically acceptable salt thereof.
 17. The method accordingto claim 1, wherein the compound of formula (I) is

or a pharmaceutically acceptable salt thereof.
 18. The method accordingto claim 1, wherein the compound of formula (I) is

or a pharmaceutically acceptable salt thereof.
 19. The method accordingto claim 1, wherein the compound of formula (I) is

or a pharmaceutically acceptable salt thereof.